Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation

ABSTRACT

The present invention provides thiazole compounds of Formula I wherein W, Y, R 0 , R 2 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 , X 3  and X 4  are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments for treating or preventing thromboembolic disorders.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a 371 of International Application No.PCT/US2013/037956, filed on Apr. 24, 2013, which claims the benefit ofU.S. Provisional Applications Ser. Nos. 61/638,577, and 61/787,680,filed on Apr. 26, 2012 and Mar. 15, 2013, respectively. The entirety ofeach of these applications is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides novel imidazothiadiazole andimidazopyridazine inhibitors of platelet aggregation which are useful inpreventing or treating thromboembolic disorders. This invention alsorelates to pharmaceutical compositions containing these compounds andmethods of using the same.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), syntheticpentasaccharides, and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®).

Current anti-platelet therapies have limitations including increasedrisk of bleeding as well as partial efficacy (relative cardiovascularrisk reduction in the 20 to 30% range). Thus, discovering and developingsafe and efficacious oral or parenteral antithrombotics for theprevention and treatment of a wide range of thromboembolic disordersremains an important goal.

Alpha-thrombin is the most potent known activator of plateletaggregation and degranulation. Activation of platelets is causallyinvolved in atherothrombotic vascular occlusions. Thrombin activatesplatelets by cleaving G-protein coupled receptors termed proteaseactivated receptors (PARs). PARs provide their own cryptic ligandpresent in the N-terminal extracellular domain that is unmasked byproteolytic cleavage, with subsequent intramolecular binding to thereceptor to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic thesequence of the newly formed N-terminus upon proteolytic activation caninduce signaling independent of receptor cleavage. Platelets are a keyplayer in atherothrombotic events. Human platelets express at least twothrombin receptors, commonly referred to as PAR1 and PAR4 Inhibitors ofPAR1 have been investigated extensively, and several compounds,including vorapaxar and atopaxar have advanced into late stage clinicaltrials. Recently, in the TRACER phase III trial in ACS patients,vorapaxar did not significantly reduce cardiovascular events, butsignificantly increased the risk of major bleeding (Tricoci, P. et al.,N. Eng. J. Med., 366(1):20-33 (2012). Thus, there remains a need todiscover new antiplatelet agents with increased efficacy and reducedbleeding side effects.

There are several early reports of preclinical studies of PAR4inhibitors. Lee, F-Y. et al., “Synthesis of1-Benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole Analogues as NovelAntiplatelet Agents”, J. Med. Chem., 44(22):3746-3749 (2001) disclosesin the abstract that the compound

“was found to be a selective and potent inhibitor or protease-activatedreceptor type 4 (PAR4)-dependent platelet activation.”

Compound 58 is also referred to as YD-3 in Wu, C-C. et al., “SelectiveInhibition of Protease-activated Receptor 4-dependent PlateletActivation by YD-3”, Thromb. Haemost., 87:1026-1033 (2002). Also, seeChen, H. S. et al., “Synthesis and platelet activity”, J. Bioorg. Med.Chem., 16:1262-1278 (2008).

EP1166785 A1 and EP0667345 disclose various pyrazole derivatives whichare useful as inhibitors of platelet aggregation.

SUMMARY OF THE INVENTION

It has been found that imidazothiadiazole and imidazopyridazinecompounds in accordance with the present invention are PAR4 antagonistswhich inhibit platelet aggregation in gamma-thrombin induced plateletaggregation assays. Moreover, a compound(s) of the present invention hasbeen shown to inhibit platelet aggregation in an alpha-thrombin inducedplatelet aggregation assay, and to inhibit thrombus formation in anarterial thrombosis model in cynomolgus monkeys.

Accordingly, the present invention provides novel imidazothiadiazoleanalogues and imidazopyridazine analogues which are PAR4 antagonists andare useful as selective inhibitors of platelet aggregation, includingstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrug esters thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugesters thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrug esters thereof.

The present invention also provides a method for the treatment orprophylaxis of thromboembolic disorders comprising administering to apatient in need of such treatment or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrug esters thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrug esters thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrug esters thereof, for themanufacture of a medicament for the treatment or prophylaxis of athromboembolic disorder.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a graph which shows the effectiveness of Example 3 ininhibiting aggregation of human washed platelets stimulated by 1.5 nMalpha-thrombin;

FIG. 1B is a graph which shows the IC₅₀ of Example 3 in inhibitingalpha-thrombin-induced platelet aggregation; and

FIG. 1C is a graph which shows the antithrombotic efficacy of Example 3in the cynomolgus monkey electrolytic injury-induced carotid arterythrombosis model.

DETAILED DESCRIPTION

In one embodiment, the present invention provides imidazothiadiazole orimidazopyridazine compounds, stereoisomers, tautomers, salts, solvatesor prodrugs thereof, of Formula I having the structure:

wherein:

-   -   W is O or S;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   C₁-C₄ alkylNH—,        -   (C₁-C₄ alkyl)₂N—,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   C₁-C₄ alkylNH—,        -   (C₁-C₄ alkyl)₂N—,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   halo-C₁-C₂ alkyl,        -   halo-C₁-C₂ alkoxy,        -   CN, and        -   OH;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy, and        -   cyano;    -   X¹ is selected from the group consisting of CH, N or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³ or N;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,        halo, OH, CN, OCF₃, OCHF₂, OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy,        halo-C₁-C₃-alkyl, which contains 1 to 5 halogens, benzyloxy        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano, and —(CH₂)_(n) ¹-phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl, or        R⁴ and R⁵ can be taken together with the carbon to which they        are attached to form a C₃-C₇ cycloalkyl ring;

is a 5-membered heteroaryl ring containing at least one O, N or S atom;

-   -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, S(═O)₂NR¹¹R¹², and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₁-C₄ alkyleneoxy,        -   C₁-C₄ alkylenethio,        -   C₁-C₄ alkyleneoxy-C₁-C₄-alkylene,        -   C₁-C₄-alkylenethio-C₁-C₄-alkylene,        -   —S—C₁-C₄-alkylene,        -   —O—C₁-C₄-alkylene,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            cyano-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², NR¹¹R¹² and C₁-C₄ alkyl;            and        -   C₅-C₁₁ spirocycloalkyl which may contain unsaturation and            optionally containing 1 to 3 heteroatoms selected from O, N            or S and substituted by 0 to 3 groups independently selected            from the group consisting of halo, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl,            and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   C₂-C₄ alkynyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   di-C₁-C₄-alkylaminophenyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to        10-membered heteroarylcarbonylamino) and —(CH₂)_(n) ¹phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        halo-C₁-C₄-alkyl, which contains 1 to 5 halogens, C₁-C₄-alkoxy,        and halo-C₁-C₄-alkoxy;

    -   or R⁶ and R⁷ can be taken together with the carbons to which        they attach to form a C₆-C₁₀ aryl ring;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5        halogens, where halo is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein Wis O.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkoxy,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl, and C₁-C₄ alkylthio;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, and        -   C₁-C₄ alkylthio;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   CF₃,        -   CF₃O,        -   CHF₂, and        -   OH;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy, and        -   cyano;    -   X¹ is selected from the group consisting of CH, N or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³ or N;    -   R³ is selected from the group consisting of H, C₁-C₄ alkoxy,        C₁-C₄ alkylthio, halo, OCF₃, OCHF₂, OCH₂F, and halo-C₁-C₂-alkyl,        which contains 1 to 5 halogens;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl, or        R⁴ and R⁵ can be taken together with the carbon to which they        are attached to form a C₃-C₇ cycloalkyl ring;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, S(═O)₂NR¹¹R¹², and C₁-C₄        alkyl substituted by 0 to 3 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, and C₁-C₄ alkylthio,        or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene,        -   C₁-C₄ alkyleneoxy,        -   C₁-C₄ alkylenethio,        -   C₁-C₄ alkyleneoxy-C₁-C₄-alkylene,        -   C₁-C₄-alkylenethio-C₁-C₄-alkylene,        -   —S—C₁-C₄-alkylene, and        -   —O—C₁-C₄-alkylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl; and        -   C₅-C₁₁ spirocycloalkyl which may contain unsaturation and            optionally containing 1 to 3 heteroatoms selected from O, N            or S and substituted by 0 to 3 groups independently selected            from the group consisting of halo, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl,            and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   C₂-C₄ alkynyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   di-C₁-C₄-alkylaminophenyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 6-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R⁷ is selected from the group consisting of H, halo, C₁-C₃        alkyl, hydroxy-C₁-C₃-alkyl, halo-C₁-C₂-alkyl, which contains 1        to 3 halogens, and halo-C₁-C₂-alkoxy;

    -   R¹⁰ is selected from the group consisting of C₁-C₃ alkyl, halo,        C₁-C₂ alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 3        halogens, where halo is F or Cl;

    -   n¹ is selected from 0, 1, 2, 3, 4 or 5; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   Y is S or CH═CH—;    -   X¹ is CH or N;    -   X², X³ and X⁴ are each independently CR³;    -   R⁰ is R¹ or R^(1a);    -   R¹ and R^(1a) are independently selected from the group        consisting of:        -   C₁-C₂ alkyl,        -   C₁-C₂ alkylthio,        -   C₁-C₂ alkoxy, and        -   halo-C₁-C₂-alkyl which contains 1 to 5 halogens;    -   R² is H;    -   R₃ is selected from the group consisting of:        -   H        -   C₁-C₂ alkoxy, and        -   halo; and    -   R⁴ and R⁵ are each H.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula IA and IB:

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IC, ID, IE and IF:

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IA.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IB.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IC.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula ID.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IE.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IF.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinR⁶ is

is selected from the group consisting of:

-   -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently selected        from the group consisting of halo, C₁-C₄ alkoxy, halo-C₁-C₄        alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl, cyano,        nitro, NR¹¹R¹², OH, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl,        hydroxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,        N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,        NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴,        (C═O)OR¹⁴, and 5-6-membered heteroaryl,    -   5- to 10-membered heteroaryl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆        cycloalkyl, cyano, nitro, NR¹¹R¹², OH,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, COOR¹⁴,        SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,        N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,        O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered        heteroaryl, and (CH₂)phenyl,    -   4- to 10-membered heterocyclyl containing carbon atoms and 1 to        2 additional heteroatoms selected from N, O, and S, and        substituted by 0 to 3 groups independently selected from the        group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or 6-membered        heteroaryl substituted by 0 to 3 groups independently selected        from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,        —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and        CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄        alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano, C₁-C₄        alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl,        C₆-C₁₀ arylcarbonyl, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴,        SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,        N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,        O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3        groups independently selected from the group consisting of halo,        C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, C₁-C₄-alkoxycarbonyl,        (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃; and    -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted by        0 to 3 groups independently selected from the group consisting        of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,        C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinR⁶ is selected from the group consisting of H, halo, OCF₃, OCHF₂,NR¹¹R¹², C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl,S(═O)₂NR¹¹R¹², and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, andC₃-C₆-cycloalkyl.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein

is selected from the group consisting of

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein:

is selected from the group consisting of

is selected from the group consisting of:

-   -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently selected        from the group consisting of halo, C₁-C₄ alkoxy, halo-C₁-C₄        alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl, cyano,        nitro, NR¹¹R¹², OH, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl,        hydroxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,        N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,        NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴,        (C═O)OR¹⁴, and 5-6-membered heteroaryl,    -   5- to 10-membered heteroaryl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆        cycloalkyl, cyano, nitro, NR¹¹R¹², OH,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, COOR¹⁴,        SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,        N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,        O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered        heteroaryl, and (CH₂)phenyl,    -   4- to 10-membered heterocyclyl containing carbon atoms and 1 to        2 additional heteroatoms selected from N, O, and S, and        substituted by 0 to 3 groups independently selected from the        group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or 6-membered        heteroaryl substituted by 0 to 3 groups independently selected        from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,        —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and        CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄        alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano, C₁-C₄        alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl,        C₆-C₁₀ arylcarbonyl, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴,        SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,        N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,        O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3        groups independently selected from the group consisting of halo,        C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, C₁-C₄-alkoxycarbonyl,        (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃; and    -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted by        0 to 3 groups independently selected from the group consisting        of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,        C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

is selected from the group consisting of

is selected from the group consisting of:

-   -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently selected        from the group consisting of halo, C₁-C₄ alkoxy, halo-C₁-C₄        alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl, cyano,        nitro, NR¹¹R¹², OH, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl,        hydroxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,        N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,        NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴,        (C═O)OR¹⁴, and 5-6-membered heteroaryl,    -   5- to 10-membered heteroaryl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆        cycloalkyl, cyano, nitro, NR¹¹R¹², OH,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, COOR¹⁴,        SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)C═O)NR¹¹R¹²,        N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,        O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered        heteroaryl, and (CH₂)phenyl,    -   4- to 10-membered heterocyclyl containing carbon atoms and 1 to        2 additional heteroatoms selected from N, O, and S, and        substituted by 0 to 3 groups independently selected from the        group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or 6-membered        heteroaryl substituted by 0 to 3 groups independently selected        from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,        —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and        CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄        alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano, C₁-C₄        alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl,        C₆-C₁₀ arylcarbonyl, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴,        SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,        N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴. O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,        O(C═O)OR¹⁴, (C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by        0 to 3 groups independently selected from the group consisting        of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,        C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃; and    -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted by        0 to 3 groups independently selected from the group consisting        of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,        C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl; and

R⁷ is selected from the group consisting of H, halo, C₁-C₄ alkyl, andhydroxy-C₁-C₄-alkyl.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O or S;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   halo-C₁-C₂ alkyl,        -   halo-C₁-C₂ alkoxy, and        -   OH;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl, and        -   C₁-C₄ alkoxy;    -   X¹ is selected from the group consisting of CH, N or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³ or N;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,        halo, OH, CN, OCF₃, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl,        which contains 1 to 5 halogens, benzyloxy substituted by 0 to 3        groups independently selected from the group consisting of halo,        C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or        6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and        cyano, and —(CH₂)_(n) ¹-phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl, or        R⁴ and R⁵ can be taken together with the carbon to which they        are attached to form a C₃-C₇ cycloalkyl ring;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, and C₁-C₅ alkyl substituted        by 0 to 7 groups independently selected from halo, CF₃, OCF₃,        OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄        alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₁-C₄ alkyleneoxy,        -   C₁-C₄ alkylenethio,        -   C₁-C₄ alkyleneoxy-C₁-C₄-alkylene,        -   C₁-C₄-alkylenethio-C₁-C₄-alkylene,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl; and        -   C₅-C₁₁ spirocycloalkyl which may contain unsaturation and            optionally containing 1 to 3 heteroatoms selected from O, N            or S and substituted by 0 to 3 groups independently selected            from the group consisting of halo, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl,            and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   C₂-C₄ alkynyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹-C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to        10-membered heteroarylcarbonylamino) and —(CH₂)_(n) ¹phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        halo-C₁-C₄-alkyl, which contains 1 to 5 halogens, C₁-C₄-alkoxy,        and halo-C₁-C₄-alkoxy;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5        halogens, where halo is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O or S;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   halo-C₁-C₂ alkyl, and        -   halo-C₁-C₂ alkoxy;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   halo, and        -   C₁-C₄ alkyl;    -   X¹ is selected from the group consisting of CH, N or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³ or N;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,        halo, OH, CN, OCF₃, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl,        which contains 1 to 5 halogens, and —(CH₂)_(n) ¹-phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl, or        R⁴ and R⁵ can be taken together with the carbon to which they        are attached to form a C₃-C₇ cycloalkyl ring;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹² and C₁-C₅ alkyl substituted by 0 to 7 groups        independently selected from halo, CF₃, OCF₃, OH,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₁-C₄ alkyleneoxy,        -   C₁-C₄ alkylenethio,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl; and        -   C₅-C₁₁ spirocycloalkyl which may contain unsaturation and            optionally containing 1 to 3 heteroatoms selected from O, N            or S and substituted by 0 to 3 groups independently selected            from the group consisting of halo, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl,            and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino) and        —(CH₂)_(n) ¹phenyl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        OCHF₂, di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        halo-C₁-C₄-alkyl, which contains 1 to 5 halogens, and        C₁-C₄-alkoxy;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo        is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2, 3 or 4; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl, and        -   halo-C₃-C₄ cycloalkyl;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl, and        -   halo-C₃-C₄ cycloalkyl;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy, and        -   halo-C₁-C₂ alkyl;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   halo, and        -   C₁-C₄ alkyl;    -   X¹ is selected from the group consisting of CH, N or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN, OCF₃,        C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl, which contains 1 to        5 halogens, and —(CH₂)_(n) ¹-phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², C₄ alkoxycarbonyl, (C═O)NR¹¹R¹² and        C₁-C₅ alkyl substituted by 0 to 7 groups independently selected        from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,        C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₁-C₄ alkyleneoxy,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl; and        -   C₅-C₁₁ spirocycloalkyl which may contain unsaturation and            optionally containing 1 to 3 heteroatoms selected from O, N            or S and substituted by 0 to 3 groups independently selected            from the group consisting of halo, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl,            and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl, and        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino and —(CH₂)_(n) ¹phenyl substituted by        0 to 3 groups independently selected from the group consisting        of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5-        or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and        cyano,

    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl        and halo-C₁-C₄-alkyl, which contains 1 to 5 halogens;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo        is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein:

-   -   W is O;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl, and        -   halo-C₁-C₂ alkyl;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   halo, and        -   C₁-C₄ alkyl;    -   X¹ is selected from the group consisting of CH, N or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN, OCF₃,        halo-C₁-C₃-alkyl, which contains 1 to 5 halogens, and —(CH₂)_(n)        ¹-phenyl substituted by 0 to 3 groups independently selected        from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, NR¹¹R¹², C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹² and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;            and        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl, and        -   phenylcarbonyl;            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl and        —(CH₂)_(n) ¹phenyl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        OCHF₂, di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, oxo, C₁-C₄        alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and        halo-C₁-C₄-alkyl, which contains 1 to 5 halogens;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo        is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl, and        -   halo-C₁-C₂ alkyl;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   halo, and        -   C₁-C₄ alkyl;    -   X¹ is selected from the group consisting of CH or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, halo-C₁-C₃-alkyl, which        contains 1 to 5 halogens, and —(CH₂)_(n) ¹-phenyl substituted by        0 to 3 groups independently selected from the group consisting        of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5-        or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and        cyano;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, OH,        NR¹¹R¹², alkoxycarbonyl, (C═O)NR¹¹R¹² and C₁-C₅ alkyl        substituted by 0 to 7 groups independently selected from halo,        CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)R¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,            O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, and            5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;            and        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   —(CR¹⁴R¹⁴)phenyl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered            heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, and        -   C₁-C₄-alkoxycarbonyl;            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)_(n) ¹phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, C₁-C₄        alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and        halo-C₁-C₄-alkyl, which contains 1 to 5 halogens;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo        is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;

R⁸ and R⁹ are independently selected from the group consisting of:

-   -   -   H,        -   C₁-C₄ alkyl, and        -   halo-C₁-C₂ alkyl;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;

    -   R² is selected from the group consisting of:        -   H, and        -   halo;

    -   X¹ is selected from the group consisting of CH or CR¹⁰;

    -   X², X³ and X⁴ are independently selected from CR³;

    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, halo-C₁-C₃-alkyl, which        contains 1 to 5 halogens, and —(CH₂)_(n) ¹-phenyl substituted by        0 to 3 groups independently selected from the group consisting        of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5-        or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and        cyano;

    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, NR¹¹R¹²,        C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹² and C₁-C₅ alkyl substituted        by 0 to 7 groups independently selected from halo, CF₃, OCF₃,        OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄        alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;            and        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl, and        -   C₁-C₄-alkoxy-C₁-C₄-alkyl;        -   alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H and C₁-C₆ alkyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)_(n) ¹phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, C₁-C₄        alkyl, hydroxy-C₁-C₄-alkyl and halo-C₁-C₄-alkyl, which contains        1 to 5 halogens;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo        is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   C₁-C₄ alkyl, and        -   halo-C₁-C₂ alkyl;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is H;    -   X¹ is selected from the group consisting of CH;    -   X², X³ and X⁴ are independently selected from CR³;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₁-C₄ alkoxy, halo, halo-C₁-C₃-alkyl, which contains 1 to 5        halogens, and —(CH₂)_(n) ¹-phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, NR¹¹R¹²,        C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹² and C₁-C₅ alkyl substituted        by 0 to 7 groups independently selected from halo, CF₃, OCF₃,        OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄        alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -    and        -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH;

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹⁻¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)OR¹⁴,            N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴,            (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;            and        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl, and        -   cyano-C₁-C₄-alkyl;            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H and C₁-C₆ alkyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)_(n) ¹phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, C₁-C₄        alkyl, hydroxy-C₁-C₄-alkyl and halo-C₁-C₄-alkyl, which contains        1 to 5 halogens;

    -   n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   C₁-C₄ alkyl, and        -   halo-C₁-C₂ alkyl;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is H;    -   X¹ is selected from the group consisting of CH;    -   X², X³ and X⁴ are independently selected from CR³;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₁-C₄ alkoxy, halo and halo-C₁-C₃-alkyl, which contains 1 to 5        halogens;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, NR¹¹R¹²,        C₁-C₄ alkoxycarbonyl and C₁-C₅ alkyl substituted by 0 to 7        groups independently selected from halo, CF₃, OCF₃, OH,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -    and        -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH;

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;            and        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   hydroxy-C₁-C₄-alkyl, and        -   cyano-C₁-C₄-alkyl;            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy;

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H and C₁-C₆ alkyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)_(n) ¹phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, C₁-C₄ alkyl        and halo-C₁-C₄-alkyl, which contains 1 to 5 halogens; and

    -   n¹, at each occurrence, is selected from 0, 1 or 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein:

-   -   Y is S or —CH═CH—;    -   R¹ and R^(1a) are selected from the group consisting of:        -   CH₃,        -   SCH₃,        -   OCH₃,        -   CH(CH₃)F,        -   C(CH₃)F₂, and        -   CF₃;    -   X¹ is CH or N;    -   X² and X⁴ are each CH; and    -   X³ is CR³ where R³ is OCH₃, F or Cl;    -   the 5-membered heteroaryl ring

-   -    is selected from the group consisting of

-   -   R⁶ is selected from the group consisting of:        -   a) phenyl or substituted phenyl, which is selected from the            group consisting of

-   -   -   b) heterocyclyl, which is selected from the group consisting            of

-   -   -   c) substituted heterocyclyl, which is selected from the            group consisting of

-   -   -   d) cycloalkyl, which is selected from the group consisting            of

-   -   -   e) heteroaryl-C₁-C₃-alkyl, which is

-   -   -   f) heteroaryl, which is selected from the group consisting            of

-   -   -   g) substituted heteroaryl, which is selected from the group            consisting of

-   -   -   h) haloalkyl, which is —CF₃,        -   i) halo, which is Br,        -   j) alkoxyalkoxyalkyl, which is —CH₂OCH₂CH₂OCH₃,        -   k) alkyl which is selected from —CH₂CH₃ or CH₃,        -   l) aryl-C₁-C₃-alkyl, which is selected from

-   -   -   m) H,        -   n) —NR¹¹R¹², which is selected from the group consisting of

-   -   R⁷ is selected from the group consisting of H and C₁-C₄ alkyl.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

is selected from the group consisting of

-   -   substituted phenyl, which is selected from the group consisting        of

-   -   heteroaryl, which is selected from the group consisting of

-   -   heterocyclyl, which is selected from the group consisting of

-   -    and    -   cycloalkyl, which is

and

-   -   R⁷ is selected from H or C₁-C₄ alkyl.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

is selected from the group consisting of

-   -   R⁶ is selected from the group consisting of H, halo, CF₃, OCF₃,        OCHF₂, C₃-C₆ cycloalkyloxy, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄        alkoxycarbonyl, C(═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl,        S(═O)₂NR¹¹R¹², phenyloxy, phenylthio, phenyl-C₁-C₄-alkoxy,        heteroaryl-C₁-C₄-alkoxy, and phenyl-C₁-C₄-alkyl; and    -   R⁷ is H or CH₃.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein:

-   -   Y is S;    -   X¹ is CH;    -   R² is H;    -   R⁴ and R⁵ are each H;    -   R¹ is OCH₃ or —CH(CH₃)F;    -   R³ is OCH₃ or F;    -   R⁴ and R⁵ are each H;

-   -   R⁶ is

-   -    and    -   R⁷ is H or CH₃.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   Y is CH═CH;    -   X¹ is CH;    -   R² is H;    -   R⁴ and R⁵ are each H;    -   R^(1a) is CH₃;    -   R³ is OCH₃ or F;

-   -   R⁶ is selected from the group consisting of

-   -    and —CH₂CH₃; and    -   R⁷ is H.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   R⁰ is C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₂-alkyl, which        contains 1 to 5 halogens, where halo is F or Cl, or halo;    -   R² is H;    -   R³ is C₁-C₄ alkoxy or halo;    -   R⁴ is H; and    -   R⁵ is H.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   X¹ is CH;

-   -    where R¹ or R^(1a) is independently selected from C₁-C₄ alkyl,        halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl, or C₁-C₃ alkoxy;    -   R⁸ and R⁹ are each H; and    -   R² is H.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein:

-   -   X¹ is CH or N;    -   R³ is OCH₃ or fluoro; and    -   R⁶ is        -   C₁-C₃ alkyl,        -   halo-C₁-C₂-alkyl,        -   phenyl,        -   phenyl substituted with 0 to 3 substituents selected from 1            or 2 halo groups, halo-C₁-C₂ alkyl which contains 1 to 5            halogens, C₁-C₃ alkyl and C₁-C₃ alkoxy, or

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein

is a 5-membered heteroaryl ring containing one or two N atoms and one Satom or three N atoms.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   X¹ is CH;    -   R¹ is OCH₃, CH₃, C₂H₅ or i-C₃H₇;    -   R^(1a) is CH₃;    -   R² is H;    -   R³ is OCHF₂, OCH₃ or F;

-   -    and    -   R⁸ and R⁹ are each H.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

where

-   -   R¹ is OCH₃, —CHFCH₃, or —CF₂CH₃;    -   R² is H;    -   X¹ is CH;    -   R³ is OCH₃ or fluoro;

-   -   R⁶ is selected from the group consisting of:        -   a) phenyl substituted by 0 to 3 groups independently            selected from the group consisting of fluoro, chloro, —CH₃,            —CF₃, OH, cyano, —CH₂CN, —OCH₃, —OCF₃, —CH₂OH, —C(CH₃)₂OH,            —SO₂CH₃ and (C═O)NR¹¹R¹², wherein NR¹¹R¹² is selected from:

-   -   -   b) pyridinyl or pyrimidinyl substituted by 0 to 3 groups            independently selected from the group consisting of fluoro,            chloro, —CH₃ and —OCH₃;        -   c) tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl,            morpholinyl, thiomorpholinyl or piperazine substituted by 0            to 3 groups independently selected from the group consisting            of fluoro, OH, —CH₃ and —NH₂; and        -   d) cyclohexyl substituted by 0 to 3 groups independently            selected from the group consisting of fluoro, OH and NH₂;            and

    -   R⁷ is selected from the group consisting of H and —CH₃.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein:

where

-   -   R¹ is CH₃;    -   X¹ is CH;    -   R² is H;    -   R³ is OCH₃;

-   -   R⁶ is selected from the group consisting of:        -   a) phenyl substituted by 0 to 3 groups independently            selected from the group consisting of chloro, —CF₃, cyano,            —OCH₃, —OCF₃, —SO₂CH₃ and (C═O)N(CH₃)₂;        -   b) pyridinyl or pyrimidinyl substituted by 0 to 3 groups            independently selected from the group consisting of fluoro,            chloro, —CH₃ and —OCH₃; and        -   c) piperidinyl, morpholinyl or thiomorpholinyl substituted            by 0 to 3 groups independently selected from the group            consisting of fluoro, OH, —CH₃ and —NH₂;    -   R⁷ is selected from the group consisting of H and —CH₃; and    -   R⁸ and R⁹ are each H.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O or S;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   halo-C₁-C₂ alkyl, and        -   halo-C₁-C₂ alkoxy;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₃ alkyl, and        -   C₁-C₂ alkoxy;    -   X¹ is selected from the group consisting of CH, N or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³ or N;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,        halo, OH, CN, OCF₃, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl,        which contains 1 to 5 halogens, benzyloxy substituted by 0 to 3        groups independently selected from the group consisting of halo,        C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or        6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and        cyano, and —(CH₂)_(n) ¹-phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl, or        R⁴ and R⁵ can be taken together with the carbon to which they        are attached to form a C₃-C₇ cycloalkyl ring;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, and C₁-C₅ alkyl substituted        by 0 to 7 groups independently selected from halo, CF₃, OCF₃,        OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄        alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,        -   —O—,        -   —S—,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₁-C₄ alkyleneoxy,        -   C₁-C₄ alkylenethio,        -   C₁-C₄ alkyleneoxy-C₁-C₄-alkylene,        -   C₁-C₄-alkylenethio-C₁-C₄-alkylene,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl; and        -   C₅-C₁₁ spirocycloalkyl which may contain unsaturation and            optionally containing 1 to 3 heteroatoms selected from O, N            or S and substituted by 0 to 3 groups independently selected            from the group consisting of halo, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl,            and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   C₂-C₄ alkynyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   (CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to        10-membered heteroarylcarbonylamino) and —(CH₂)_(n) ¹phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        halo-C₁-C₄-alkyl, which contains 1 to 5 halogens, C₁-C₄-alkoxy,        and halo-C₁-C₄-alkoxy;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5        halogens, where halo is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O or S;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   halo-C₁-C₂ alkyl, and        -   halo-C₁-C₂ alkoxy;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is selected from the group consisting of:        -   H,        -   fluoro,        -   chloro, and        -   CH₃;    -   X¹ is selected from the group consisting of CH, N or CR¹⁰;    -   X², X³ and X⁴ are independently selected from CR³ or N;    -   R³ is selected from the group consisting of H, C₁-C₃ alkyl,        C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylthio,        halo, OH, CN, OCF₃, and halo-C₁-C₃-alkyl, which contains 1 to 5        halogens;    -   R⁴ and R⁵ are independently selected from H and C₁-C₃ alkyl, or        R⁴ and R⁵ can be taken together with the carbon to which they        are attached to form a cyclopropyl ring;

-   -    is a 5-membered heteroaryl ring containing at least one O, N or        S atom;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹² and C₁-C₅ alkyl substituted by 0 to 7 groups        independently selected from halo, CF₃, OCF₃, OH,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₁-C₄ alkyleneoxy,        -   C₁-C₄ alkylenethio,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)OR¹⁴, (C═O)R¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl; and        -   C₅-C₁₁ spirocycloalkyl which may contain unsaturation and            optionally containing 1 to 3 heteroatoms selected from O, N            or S and substituted by 0 to 3 groups independently selected            from the group consisting of halo, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl,            and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino) and        —(CH₂)_(n) ¹phenyl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        OCHF₂, di-C₁-C₄-alkylamino, and cyano,

    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        halo-C₁-C₄-alkyl, which contains 1 to 5 halogens, and        C₁-C₄-alkoxy;

    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo        is F or Cl;

    -   n¹, at each occurrence, is selected from 0, 1, 2, 3 or 4; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein:

-   -   W is O;    -   R⁹ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₂ alkyl,        -   cyclopropyl,        -   C₁-C₂ alkoxy,        -   C₁-C₂ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl, and        -   halo-C₃-C₄ cycloalkyl;

R^(1a) is independently selected from the group consisting of:

-   -   -   H,        -   halo,        -   C₁-C₂ alkyl,        -   cyclopropyl,        -   C₁-C₂ alkoxy,        -   C₁-C₂ alkylthio,        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl, and        -   halo-C₃-C₄ cycloalkyl;

    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   fluoro,        -   chloro,        -   C₁-C₃ alkyl,        -   C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkyl;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;

    -   R² is H;

    -   X¹ is selected from the group consisting of CH or N;

    -   X², X³ and X⁴ are independently selected from CR³;

    -   R³ is selected from the group consisting of H, C₁-C₃ alkyl,        C₁-C₃ alkoxy, fluoro, chloro, OCF₃, and halo-C₁-C₂-alkyl, which        contains 1 to 5 halogens;

    -   R⁴ and R⁵ are independently selected from H and methyl;

-   -    is a 5-membered heteroaryl ring selected from thiazole,        thiadiazole, oxazole, oxadiazole, and triazole;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹²        and C₁-C₅ alkyl substituted by 0 to 7 groups independently        selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄        alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH,        -   C₁-C₄ alkyleneoxy,        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl; and        -   C₅-C₁₁ spirocycloalkyl which may contain unsaturation and            optionally containing 1 to 3 heteroatoms selected from O, N            or S and substituted by 0 to 3 groups independently selected            from the group consisting of halo, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl,            and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl, and        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino and —(CH₂)_(n) ¹phenyl substituted by        0 to 3 groups independently selected from the group consisting        of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5-        or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and        cyano,

    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        oxo, C₁-C₃ alkyl, hydroxy-C₁-C₃-alkyl, and halo-C₁-C₂-alkyl,        which contains 1 to 5 halogens;

    -   n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CR⁸═CR⁹—;    -   R¹ is independently selected from the group consisting of:        -   C₁-C₂ alkyl,        -   C₁-C₂ alkoxy,        -   C₁-C₂ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R^(1a) is independently selected from the group consisting of:        -   H,        -   fluoro,        -   chloro,        -   C₁-C₂ alkyl,        -   C₁-C₂ alkoxy,        -   C₁-C₂ alkylthio, and        -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo            is F or Cl;    -   R⁸ and R⁹ are independently selected from the group consisting        of:        -   H,        -   fluoro,        -   chloro,        -   CH₃,        -   OCH₃,        -   CF₃, and        -   CHF₂;            provided that at least one of R^(1a), R⁸ and R⁹ is other            than H;    -   R² is H;    -   X¹ is selected from the group consisting of CH or N;    -   X² and X⁴ are CH;    -   X³ is CR³;    -   R³ is selected from the group consisting of H, C₁-C₃ alkyl,        C₁-C₃ alkoxy, fluoro, chloro, OCF₃, and halo-C₁-C₂-alkyl, which        contains 1 to 5 halogens;    -   R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

-   -    is a 5-membered heteroaryl ring selected from thiazole,        thiadiazole, oxazole, oxadiazole, and triazole;    -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, NR¹¹R¹², C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹² and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a linker, which is selected from:        -   a single bond,

-   -   -   C₁-C₄ alkylene substituted by 0 to 4 groups independently            selected from halo or OH, and        -   C₂-C₆ alkenylene, and

    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;            and        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl;

    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   (CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by            0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl, and        -   phenylcarbonyl;            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 8-membered heterocyclic            ring containing carbon atoms substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy,            and 0 to 2 additional heteroatoms selected from N, NR¹³, O            and S(O)_(p);

    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, and C₁-C₃ alkyl;

    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₃ alkyl, and halo-C₁-C₂-alkyl;

    -   R⁷ is selected from the group consisting of H, fluoro, chloro,        oxo, C₁-C₃ alkyl, hydroxy-C₁-C₃-alkyl, and halo-C₁-C₂-alkyl,        which contains 1 to 5 halogens;

    -   n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

    -   p, at each occurrence, is selected from 0, 1 and 2.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

-   -   W is O;    -   R⁰ is R¹ or R^(1a);    -   Y is S or —CH═CH—;    -   R¹ is independently selected from the group consisting of:        -   CH₃,        -   OCH₃,        -   SCH₃,        -   CHFCH₃, and        -   CF₂CH₃;    -   R^(1a) is independently selected from the group consisting of:        -   chloro,        -   CH₃, and        -   OCH₃,    -   R² is H;    -   X¹ is CH;    -   X² and X⁴ are CH;    -   X³ is CR³;    -   R³ is selected from the group consisting of OCH₃, fluoro, and        chloro;    -   R⁴ and R⁵ are independently selected from H and CH₃;

-   -    is a 5-membered heteroaryl ring selected from thiazole and        oxazole;    -   R⁶ is selected from the group consisting of, NR¹¹R¹², and C₁-C₅        alkyl substituted by 0 to 3 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where D is a single bond;    -   B is selected from the group consisting of:        -   C₆-C₁₀ aryl substituted by 0 to 3 groups independently            selected from the group consisting of halo, C₁-C₄ alkoxy,            halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆            cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and 5-6-membered heteroaryl,        -   5- to 10-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ alkyl, halo-C₁-C₄            alkyl, C₃-C₆ cycloalkyl, cyano, nitro, NR¹¹R¹², OH,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,            COOR¹⁴, SO₂R¹⁴, (C═O)NR¹¹R¹², SO₂NR¹¹R¹²,            N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,            NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and            (CH₂)phenyl,        -   4- to 10-membered heterocyclyl containing carbon atoms and 1            to 2 additional heteroatoms selected from N, O, and S, and            substituted by 0 to 3 groups independently selected from the            group consisting of halo, oxo, —(CHR¹³)_(n) ¹-5- or            6-membered heteroaryl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, —(CHR¹³)_(n) ¹-4- to            10-membered-heterocyclyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and            CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, halo-C₁-C₄            alkoxy, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR₁₁R₁₂, cyano,            C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆            cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,            C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,            (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,            N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴,            O(C═O)R¹⁴, (C═O)OR¹⁴, and C₆-C₁₀ aryl substituted by 0 to 3            groups independently selected from the group consisting of            halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃;            and        -   C₃-C₆ cycloalkyl which may contain unsaturation, substituted            by 0 to 3 groups independently selected from the group            consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl,            OH, oxo, hydroxy-C₁-C₄-alkyl, C₆-C₁₀ aryl, COOH, oxo,            C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², and C₁-C₄ alkyl;    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, and        -   C₁-C₄-alkoxycarbonyl;            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 7-membered heterocyclic            ring containing carbon atoms substituted by 0 to 2 groups            independently selected from the group consisting of halo,            CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, OH, oxo, hydroxy-C₁-C₂-alkyl,            C₁-C₃ alkyl and C₁-C₃ alkoxy, and 0 to 2 additional            heteroatoms selected from N, NR¹³, O and S(O)_(p);    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, and C₁-C₃ alkyl;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, and C₁-C₃ alkyl    -   R⁷ is selected from the group consisting of H, fluoro, chloro,        C₁-C₃ alkyl, hydroxy-C₁-C₃-alkyl, and halo-C₁-C₂-alkyl, which        contains 1 to 5 halogens;    -   n¹, at each occurrence, is selected from 0, 1, 2 or 3; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are selected from the examples, preferably Examples 3 to318.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are selected from:

Preferably, PAR4 compounds of the invention have IC₅₀s in the FLIPRAssay (described hereinafter) of about 10 μM, preferably 5 μM or less,more preferably 500 nM or less, and even more preferably 10 nM or less.Activity data for compounds of the present invention is presented in thetables of Example F.

In some embodiments, the present invention provides at least onecompound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate, or prodrug ester thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition, which includes a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of Formula I, IA, IB, IC,ID, IE, or IF, preferably, a compound selected from one of the examples,more preferably, Examples 3 to 318, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,alone or in combination with another therapeutic agent.

In some embodiments, the present invention provides a pharmaceuticalcomposition which further includes another therapeutic agent(s). In apreferred embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are P2Y12 antagonists and/or aspirin. Preferably,the P2Y12 antagonists are clopidogrel, ticagrelor, or prasugrel. Inanother preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent(s)are an anticoagulant or a combination thereof. Preferably, theanticoagulant agent(s) are FXa inhibitors or thrombin inhibitors.Preferably, the FXa inhibitors are apixaban or rivaroxaban. Preferably,the thrombin inhibitor is dabigatran.

In some embodiments, the present invention provides a method for thetreatment or prophylaxis of a thromboembolic disorder which includes thestep of administering to a subject (for example, a human) in need ofsuch treatment or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugesters thereof.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IA, IB, IC,ID, IE, or IF, preferably, a compound selected from one of the examples,more preferably, Examples 3 to 318, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, cerebrovascular thromboembolicdisorders, and thromboembolic disorders in the chambers of the heart orin the peripheral circulation.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IA, IB, IC,ID, IE, or IF, preferably, a compound selected from one of the examples,more preferably, Examples 3 to 318, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of acute coronary syndrome, unstable angina, stable angina,ST-elevated myocardial infarction, non-ST-elevated myocardialinfarction, atrial fibrillation, myocardial infarction, transientischemic attack, stroke, atherosclerosis, peripheral arterial disease,venous thrombosis, deep vein thrombosis, thrombophlebitis, arterialembolism, coronary arterial thrombosis, cerebral arterial thrombosis,cerebral embolism, kidney embolism, pulmonary embolism, cancer-relatedthrombosis, and thrombosis resulting from medical implants, devices, andprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IA, IB, IC,ID, IE, or IF, preferably, a compound selected from one of the examples,more preferably, Examples 3 to 318, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of acute coronary syndrome, unstable angina, stable angina,ST-elevated myocardial infarction, and non-ST-elevated myocardialinfarction.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IA, IB, IC,ID, IE, or IF, preferably, a compound selected from one of the examples,more preferably, Examples 3 to 318, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of transient ischemic attack and stroke.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IA, IB, IC,ID, IE, or IF, preferably, a compound selected from one of the examples,more preferably, Examples 3 to 318, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is peripheral arterial disease.

In some embodiments, the present invention includes a method asdescribed above wherein the thromboembolic disorder is selected fromunstable angina, an acute coronary syndrome, atrial fibrillation, firstmyocardial infarction, recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.

In some embodiments, the present invention includes a method ofinhibiting or preventing platelet aggregation, which includes the stepof administering to a subject (such as a human) in need thereof atherapeutically effective amount of a PAR4 antagonist, which is acompound of Formula I, IA, IB, IC, ID, IE, or IF, preferably, a compoundselected from one of the examples, more preferably, Examples 3 to 318,of the invention.

Other Embodiments of the Invention

In some embodiments, the present invention provides a process for makinga compound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug ester thereof.

In some embodiments, the present invention provides an intermediate formaking a compound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug ester thereof.

In some embodiments, the invention provides a method of treatment orprophylaxis of a thromboembolic disorder involving administering to asubject in need thereof (e.g., a human) a therapeutically effectiveamount of a compound that binds to PAR4 (such as a compound of Formula Iof the invention) and inhibits PAR4 cleavage and/or signaling, whereinsaid subject has a dual PAR1/PAR4 platelet receptor repertoire.

In some embodiments, the present invention provides a compound of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrug esters thereof, for use intherapy for the treatment or prophylaxis of a thromboembolic disorder.

In some embodiments, the present invention also provides the use of acompound of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrug esters thereof,for the manufacture of a medicament for the treatment or prophylaxis ofa thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Chemistry

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis- andtrans-geometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated. When nospecific mention is made of the configuration (cis, trans or R or S) ofa compound (or of an asymmetric carbon), then any one of the isomers ora mixture of more than one isomer is intended. The processes forpreparation can use racemates, enantiomers, or diastereomers as startingmaterials. All processes used to prepare compounds of the presentinvention and intermediates made therein are considered to be part ofthe present invention. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods, for example, bychromatography or fractional crystallization. Compounds of the presentinvention, and salts thereof, may exist in multiple tautomeric forms, inwhich hydrogen atoms are transposed to other parts of the molecules andthe chemical bonds between the atoms of the molecules are consequentlyrearranged. It should be understood that all tautomeric forms, insofaras they may exist, are included within the invention.

The molecular weight of compounds of the present invention is preferablyless than about 800 grams per mole.

As used herein, the term “alkyl” or “alkylene”, alone or as part ofanother group, is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having from 1 to 10 carbons orthe specified number of carbon atoms. For example, “C₁₋₁₀ alkyl” (oralkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉,and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl” denotesalkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted orsubstituted with at least one hydrogen being replaced by anotherchemical group. Example alkyl groups include, but are not limited to,methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl(e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl,isopentyl, neopentyl), as well as chain isomers thereof, and the like aswell as such groups which may optionally include 1 to 4 substituentssuch as halo, for example F, Br, Cl, or I, or CF₃, alkyl, alkoxy, aryl,aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy,hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl,alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol,haloalkyl, trihaloalkyl, and/or alkylthio as well as (═O), OR_(a),SR_(a), (═S), —NR_(a)R_(b), —N(alkyl)₃ ⁺, —NR_(a)SO₂, —NR_(a)SO₂R_(c),—SO₂R_(c)—SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H, —PO(OH)₂,—C(═O)R_(a), —CO₂R_(a), —C(═O)NR_(a)R_(b), —C(═O)(C₁-C₄alkylene)NR_(a)R_(b), —C(═O)NR_(a)(SO₂)R_(b), —CO₂(C₁-C₄alkylene)NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b), —NR_(a)(C₁-C₄alkylene)CO₂R_(b), ═N—OH, ═N—O-alkyl, wherein R_(a) and R_(b) are thesame or different and are independently selected from hydrogen, alkyl,alkenyl, CO₂H, CO₂(alkyl), C₃-C₇cycloalkyl, phenyl, benzyl, phenylethyl,naphthyl, a 4- to 7-membered heterocyclo, or a 5- to 6-memberedheteroaryl, or when attached to the same nitrogen atom may join to forma heterocyclo or heteroaryl, and R_(c) is selected from same groups asR_(a) and R_(b) but is not hydrogen. Each group R_(a) and R_(b) whenother than hydrogen, and each R_(c) group optionally has up to threefurther substituents attached at any available carbon or nitrogen atomof R_(a), R_(b), and/or R_(c), said substituent(s) being the same ordifferent and are independently selected from the group consisting of(C₁-C₆)alkyl, (C₂-C₆)alkenyl, hydroxy, halogen, cyano, nitro, CF₃,O(C₁-C₆ alkyl), OCF₃, C(═O)H, C(═O)(C₁-C₆ alkyl), CO₂H, CO₂(C₁-C₆alkyl), NHCO₂(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂, NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, N(CH₃)₃ ⁺, SO₂(C₁-C₆ alkyl), C(═O)(C₁-C₄ alkylene)NH₂,C(═O)(C₁-C₄ alkylene)NH(alkyl), C(═O)(C₁-C₄ alkylene)N(C₁-C₄ alkyl)₂,C₃-C₇ cycloalkyl, phenyl, benzyl, phenylethyl, phenyloxy, benzyloxy,naphthyl, a 4- to 7-membered heterocyclo, or a 5- to 6-memberedheteroaryl. When a substituted alkyl is substituted with an aryl,heterocyclo, cycloalkyl, or heteroaryl group, said ringed systems are asdefined below and thus may have zero, one, two, or three substituents,also as defined below.

“Alkenyl” or “alkenylene”, alone or as part of another group, isintended to include hydrocarbon chains of either straight or branchedconfiguration and having one or more carbon-carbon double bonds that mayoccur in any stable point along the chain. For example, “C₂₋₆ alkenyl”(or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenylgroups. Examples of alkenyl include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, and 4-methyl-3-pentenyl, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonyl-amino, nitro, cyano, thiol, and/or alkylthio.

“Alkynyl” or “alkynylene”, alone or as part of another group, isintended to include hydrocarbon chains of either straight or branchedconfiguration and having one or more carbon-carbon triple bonds that mayoccur in any stable point along the chain. For example, “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl, andwhich may be optionally substituted with 1 to 4 substituents, namely,halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino,alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio.

The term “alkoxy” or “alkyloxy”, alone or as part of another group,refers to an —O-alkyl group, where alkyl is as defined above. “C₁₋₆alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆alkoxy groups. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.Similarly, “alkylthio” or “thioalkoxy”, alone or as part of anothergroup, represents an alkyl group or alkoxy group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example methyl-S— and ethyl-S—.

“Halo” or “halogen”, alone or as part of another group, includes fluoro,chloro, bromo, and iodo.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 to 7 halogens, preferably 1 to 4halogens, preferably F and/or Cl. Examples of haloalkyl include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,trichloromethyl, pentafluoroethyl, pentachloroethyl, 1,1-difluoroethyl,1-fluoroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, andheptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” thatis intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 to 7 fluorine atoms, preferably 1 to 4fluorine atoms.

“Halo-C₁-C₂-alkoxy” or “haloalkyloxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (orbicycloalkyl), and tricyclic alkyl, containing a total of 3 to 10carbons forming the ring (C₃-C₁₀ cycloalkyl), and which may be fused to1 or 2 aromatic rings as described for aryl, which includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, cyclododecyl, cyclohexenyl, norbornyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents for alkyl, as well as such groups including 2free bonds and thus are linking groups.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring,any of which may be saturated, partially unsaturated, unsaturated oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, andtetrahydronaphthyl (tetralin). As shown above, bridged rings are alsoincluded in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).Preferred carbocycles, unless otherwise specified, are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term“carbocycle” is used, it is intended to include “aryl”. A bridged ringoccurs when one or more carbon atoms link two non-adjacent carbon atoms.Preferred bridges are one or two carbon atoms. It is noted that a bridgealways converts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.Unless otherwise specified, “aryl”, “C₆₋₁₀ aryl” or “aromatic residue”may be unsubstituted or substituted with 1 to 3 groups selected from OH,OC₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃,OCHF₂, C(═C)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₃ alkyl, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclo” or “heterocyclic”group is intended to mean a stable 4- to 14-membered monocyclic,bicyclic or tricyclic heterocyclic ring which is saturated or partiallyunsaturated and which consists of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, NH, Oand S and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may optionally be substituted on carbon or on anitrogen atom if the resulting compound is stable, with 1 to 3 groupsselected from OH, OC₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H,N(CH₃)₂, CF₃, OCF₃, OCHF₂, ═O, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃,C₁-C₃ alkyl, CO₂H and CO₂CH₃. A nitrogen in the heterocycle mayoptionally be quaternized. It is preferred that when the total number ofS and O atoms in the heterocycle exceeds 1, then these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand O atoms in the heterocycle is not more than 1. Spiro and bridgedrings are also included in the definition of heterocycle. A bridged ringoccurs when one or more atoms (i.e., C, O, N, or S) link twonon-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge. When the term “heterocycle” is used, itis not intended to include heteroaryl.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, and the like.

Exemplary bicyclic heterocyclo groups include quinuclidinyl.

Preferred heterocyclo groups include

which optionally may be substituted.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are unsubstitutedor substituted with 1 to 3 groups selected from OH, OC₁-C₃ alkoxy, Cl,F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, OCHF₂, ═O,C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₃ alkyl, CO₂H and CO₂CH₃. Thenitrogen atom is substituted or unsubstituted (i.e., N or NR wherein Ris H or another substituent, if defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). Bridged rings are also included in the definition ofheteroaryl. A bridged ring occurs when one or more atoms (i.e., C, O, N,or S) link two non-adjacent carbon or nitrogen atoms. Examples ofbridged rings include, but are not limited to, one carbon atom, twocarbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

Preferred heteroaryl groups include

and the like.

When the term “unsaturated” is used herein to refer to a ring or group,which group may be fully unsaturated or partially unsaturated.

The term “acyl” alone or as part of another group refers to a carbonylgroup linked to an organic radical, more particularly, the groupC(═O)R_(e), as well as the bivalent groups —C(═O)— or —C(═O)R_(e)—,which are linked to organic radicals. The group R_(e) can be selectedfrom alkyl, alkenyl, alkynyl, aminoalkyl, substituted alkyl, substitutedalkenyl, or substituted alkynyl, as defined herein, or when appropriate,the corresponding bivalent group, e.g., alkylene, alkenylene, and thelike.

The designation

attached to a ring or other group refers to a free bond or linkinggroup.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative. In cases in which there are quaternary carbonatoms in compounds of the present invention, these can be replaced bysilicon atoms, provided they do not form Si—N or Si—O bonds.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0 to 3 R^(3a), then said group mayoptionally be substituted with up to three R^(3a) groups, and at eachoccurrence R^(3a) is selected independently from the definition ofR^(3a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, L. V., Jr.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design andDevelopment, pp. 113-191, Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and

f) Rautio, J (Editor). Prodrugs and Targeted Delivery (Methods andPrinciples in Medicinal Chemistry), Vol 47, Wiley-VCH, 2011.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced(2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism.Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,Switzerland (2003); Wermuth, C. G., ed., The Practice of MedicinalChemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

Isotopically labeled compounds of the present invention, i.e., whereinone or more of the atoms described are replaced by an isotope of thatatom (e.g., ¹²C replaced by ¹³C or by ¹⁴C; and isotopes of hydrogenincluding tritium and deuterium), are also provided herein. Suchcompounds have a variety of potential uses, e.g., as standards andreagents in determining the ability of a potential pharmaceuticalcompound to bind to target proteins or receptors, or for imagingcompounds of this invention bound to biological receptors in vivo or invitro.

Compounds of the present invention are, subsequent to their preparation,preferably isolated and purified to obtain a composition containing anamount by weight equal to or greater than 98%, preferably 99%, compoundof the present invention (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates include, butare not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight,“mp” for melting point, “MS” or “Mass Spec” for mass spectrometry, “ESI”for electrospray ionization mass spectroscopy, “HR” for high resolution,“HRMS” for high resolution mass spectrometry, “LCMS” for liquidchromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” for thin layerchromatography, “SM” for starting material, “NMR” for nuclear magneticresonance spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “tlc” for thin layer chromatography.“α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designationsfamiliar to one skilled in the art.

Me methyl Et ethyl Pr propyl i-Pr isopropyl Bu butyl i-Bu isobutyl t-Butert-butyl Ph phenyl Bn benzyl AcOH acetic acid MeOH methanol EtOHethanol EtOAc ethyl acetate Et₂O diethyl ether i-PrOH or IPA isopropanolHOAc acetic acid BOP reagentbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateBBr₃ boron tribromide Boc tert-butyloxycarbonyl cDNA complimentary DNACDCl₃ deuterated chloroform CH₂Cl₂ dichloromethane CH₃CN acetonitrileACN acetonitrile DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2dichloroethane DCM dichloromethane DCC dicyclohexylcarbodiimide DIADdiisopropyl azodicarboxylate DIEA or DIPEA N,N-diisopropylethylamine DME1,2-dimethoxyethane DMF dimethyl formamide DMAPN,N-dimethylaminopyridine DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide EDC (or EDC•HCl)3-ethyl-3′-(dimethylamino)propyl-carbodiimide or EDCI (or hydrochlorideEDCI•HCl) or or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDAChydrochloride EDTA ethylenediaminetetraacetic acid HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HCl hydrochloric acid HEPES4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid Hex hexane HOBt orHOBT 1-hydroxybenzotriazole monohydrate Hunig's baseN,N-diisopropylethyl amine LAH lithium aluminum hydride LDA Lithiumdiisopropylamide LiHMDS Lithium bis(trimethylsilyl) amide mCPBA orm-CPBA meta-chloroperbenzoic acid NMM N-methylmorpholine Pd/C palladiumon carbon PPA polyphosphoric acid PS polystyrene PXPd2 bis[di-tert-butylphosphinous chloride-kP]di-m- chlorodichloro dipalladium PyBOP(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate TEAtriethylamine TFA trifluoroacetic acid THF tetrahydrofuran TRIStris(hydroxymethyl)aminomethane KOAc potassium acetate K₃PO₄ potassiumphosphate MgSO₄ magnesium sulfate NaCl sodium chloride NaH sodiumhydride NaHCO₃ sodium bicarbonate NaOH sodium hydroxide Na₂SO₃ sodiumsulfite Na₂SO₄ sodium sulfate NH₃ ammonia NH₄Cl ammonium chloride NH₄OHammonium hydroxide OTs tosylate, para-toluenesulfonate PBr₃ phosphoroustribromide Pd(PPh₃)₄ tetrakis(triphenylphosphine) palladium (0)(S,S)-EtDuPhosRh(I) (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium (I) trifluoromethanesulfonate

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Wuts et al. (Greene's Protective Groups In OrganicSynthesis, 4th Edition, Wiley-Interscience (2006)).

Compounds of formula I of this invention can be obtained by condensationof an amine of formula III with a ketone of formula IV which contains aleaving group Z such as a bromide, iodide or tosylate and a protectinggroup PG such as benzyl as shown in Scheme 1. Both compounds of formulaIII and IV are commercially available or can be prepared by means knownto one skilled in the art. This condensation is promoted by heating,either thermally or preferably by microwave irradiation. The protectinggroup can be removed by methods known in the art, such as BCl₃ at −78°C. in the presence of pentamethylbenzene. Subsequent alkylation usingeither an alcohol VI under Mitsunobu conditions or a bromide VII in thepresence of base such as potassium carbonate provides the compounds ofFormula I. Alcohols and bromides VI and VII are commercially availableor can be prepared by methods known in the art.

Alternatively, compounds of Formula I can be prepared from compounds offormula IX upon activation of the thiomethyl group by oxidation to asulfone VII as shown in Scheme 2. This allows introduction of a varietyof nucleophiles as groups R⁰ such as alcohols, thiols and amines in thepresence of a base such as potassium carbonate or sodium hydride eitherneat or in a polar, aprotic solvent such as dimethylformamide to givecompounds XI. Compounds XI can be converted to compounds of Formula I byremoval of the protecting group (PG) and alkylation as discussed inScheme 1.

Substituted benzofurans bearing α-bromoketone substituents at the2-position (XV) can be prepared as shown in Scheme 3. o-Hydroxybenzaldehydes XII can be prepared by methods known to one skilled in theart of organic synthesis, and can be condensed with ketones of formulaXIII bearing a leaving group Q such as chloro, bromo or tosyloxy, togive benzofurans XIV. Bromination of compounds of formula XIV affordsbromoketones XV, which can be condensed with a substitutedaminoheterocycle III according to Scheme 1 to give compounds of FormulaI. Bromoketones XV are a specific subset of compounds IV in Scheme 1.

Benzoxazole compounds of Formula I can be prepared starting fromsubstituted aminoheterocycle III and pyruvate esters of formula XVIwhich contain a leaving group Z such as a bromide, iodide or tosylate asshown in Scheme 4. Both compounds of formula III and XVI arecommercially available or are available by means known to one skilled inthe art. Following condensation and saponification of the ester to formacid XVIII, amino phenols of formula XIX are coupled to form amides ofthe formula XX, which can be cyclized under acid catalysis to formbenzoxazole compounds of formula XXI. These can be deprotected andalkylated as shown in Scheme 1 to provide compounds of Formula I.

Aminoheterocycles XXIV can be prepared from carbon disulfide (XXII) viathe thioxanthate intermediate XXIII. These aminoheterocycles are usefulfor the preparation of compounds of Formula I.

Aminoheterocycles XXX, which are useful intermediates for preparation ofcompounds of Formula I where Y=—CH₂CH₂—, can be prepared from ketoestersXXV. Cyclization with hydrazine, followed by oxidation with brominegives pyridazinones XXVII. Chlorination, displacement with hydrazine,and subsequent hydrogenation provides aminoheterocycles XXX, which are aspecific subset of compounds III in Scheme I. As such, theseaminoheterocycles are useful for the preparation of compounds of FormulaI.

EXAMPLES

The following compounds of the invention have been prepared, isolatedand characterized using the methods disclosed herein. They demonstrate apartial scope of the invention and are not meant to be limiting of thescope of the invention. In the experimental procedures, solution ratiosexpress a volume relationship, unless stated otherwise. NMR chemicalshifts (δ) are reported in parts per million (ppm). Products wereanalyzed by reverse phase analytical HPLC using the following methods:

Method A: Column: ZORBAX® XDB-C18 3.5 micron, 4.6×30 mm; Mobile Phase:A=MeOH:H₂O:TFA (95:5:05), B=MeOH:H₂O:TFA (5:95:05). Grad.: T=0:100% solvA; T=2:100% solv B; stop time: 4 min. Flow=3.0 mL/min.

Method B: Column: Agilent POROSHELL® 120; EC-C18, 2.7 um; 2.1×30 mm;Mobile Phase: Solv A: 5% MeOH: 95% H₂O+0.1% AcOH; Solv B: 95% MeOH: 5%H₂O+0.1% AcOH; Grad.: T=0:100% solv A; T=1:100% solv B; stop time: 4min. Flow=1.0 mL/min.

Method C: SunfireC18 3.5 micron column (4.6×30 mm) eluted at 3 mL/minwith a 2 min. gradient from 100% A to 100% B (A: 5% methanol, 94.95%water, 0.05% TFA; B: 5% water, 94.95% methanol, 0.05% TFA, UV 220 nm).

Method D: Eclipse XDB-C18 3.5 micron column (4.6×30 mm) eluted at 3mL/min with a 2 min gradient from 100% A to 100% B (A: 5% methanol,94.95% water, 0.05% TFA; B: 5% water, 94.95% methanol, 0.05% TFA, UV 220nm).

Method E: Eclipse XDB-C18 3.5 micron column (4.6×30 mm) eluted at 3mL/min with a 2 min gradient from 100% A to 100% B (A: 5% acetonitrile,94.95% water, 0.05% TFA; B: 5% water, 94.95% acetonitrile, 0.05% TFA, UV220 nm).

Method F: ZORBAX® SB-Phenyl 3.5 micron column (4.6×50 mm) eluted at 3mL/min with a 2 min gradient from 100% A to 100% B (A: 5% methanol,94.95% water, 0.05% TFA; B: 5% water, 94.95% methanol, 0.05% TFA, UV 220nm).

Method G: Waters BEH C18 column (2.0×50 mm, 1.7-μm particles); MobilePhase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile PhaseB: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40° C.;Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% B; Flow: 0.5 mL/min.

Method H: Waters BEH C18 column (2.0×50 mm, 1.7-μm particles); MobilePhase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min.

Purification of products by reverse phase preparative HPLC was doneusing the following method:

Method A: Column: ZORBAX® SB-C18 PrepHT, 5 micron, 21.2×100 mm; MobilePhase: A=MeOH:H₂O:TFA (5:95:0.05), B=MeOH:H₂O:TFA (95:5:0.05). Grad.: 0to 2 min: isocratic 25% solvent B; 8 min gradient of 25 to 100% solventB; stop time=15 min. Flow=20 mL/min, detection at UV 220 nm.

Example 12-Methoxy-6-(6-methoxy-4-((2-methylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

1A. (2-Methylthiazol-4-yl)methanol

A solution of 2-methyl-thiazole-4-carboxylic acid ethyl ester (1.26 g,7.36 mmol) in ethyl ether (10 mL) was cooled to −78° C. and treated witha solution of LAH (0.83 g, 21.9 mmol) in dry THF (30 mL) added dropwiseover 10 min. After 3 hours, at −78° C., the mixture was quenched withsat. Na₂SO₄ (app. 20 mL). The mixture was allowed to warm up to 22° C.and was extracted with ethyl ether (4×50 mL). The combined extracts werewashed with brine, dried over anhydrous MgSO₄ and concentrated to givean oil. Filtration on a silica gel pad (3×7 cm) and elution with ethylacetate gave an oil which was distilled to afford the title material(0.664 g, 70%) as an oil which crystallized. B.p. 60-70° C./0.2 torr.HRMS(ESI) calcd for C₅H₈NOS [M+H]⁺ m/z 130.0321, found 130.0342. ¹H NMR(CDCl₃, 600 MHz) δ 6.99 (d, J=0.8 Hz, 1H), 4.70 (s, 1H), 2.98 (br s,1H), 2.68 (s, 3H).

1B. 5-(Benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one

A solution of5-hydroxy-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (30.00 g,0.134 mol, see Kamisuki, S. et al., Tetrahedron, 60:5695-5700 (2004) forpreparation) in N,N-dimethylformamide (400 mL) was treated with powderedanhydrous potassium carbonate (19.41 g, 0.14 mol) added all at once. Theresulting mixture was stirred in vacuo for 10 min. and then flushed withnitrogen. The reaction flask was placed in a water bath (22° C.) andtreated with benzyl bromide (24.03 g, 0.14 mol) added dropwise over 15min. The resulting mixture was then stirred at 22° C. for 18 h (nostarting material left by tlc). The solid was filtered and washed withN,N-dimethylformamide. The filtrate was evaporated in vacuo and theresidual oil was diluted with ethyl acetate (500 mL), washed with cold0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. Afterdrying over anhydrous magnesium sulfate, evaporation of the solvent gavea thick syrup. Crystallization form ethyl acetate (50 mL) and hexane(150 mL) gave 35.17 g of5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one aslarge colorless prisms. Chromatography of the mother liquors on silicagel (4×13 cm, elution toluene-ethyl acetate 0-5%) gave 6.64 g ofadditional material to afford a total yield of 41.81 g (99%). HRMS(ESI)calcd for C₁₈H₁₉O₅ [M+H]⁺ m/z 315.1227, found 315.1386. ¹H NMR (CDCl₃,600 MHz) δ 1.68 (s, 6H), 3.77 (s, 3H), 5.19 (s, 2H), 5.19 (s, 2H), 6.04(d, J=2.03 Hz, 1H), 6.15 (d, J=2.03 Hz, 1H), 7.27 (broad t, 1H), 7.36(broad t, 2H), 7.52 (broad d, 2H).

1C. 2-(Benzyloxy)-6-hydroxy-4-methoxybenzaldehyde

A solution of5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one(Example 1B, 6.76 g, 21.5 mmol) in dichloromethane (120 mL) was cooledto −78° C. and treated with 43 mL (64.5 mmol) of a 1.5 M solution ofdiisobutylaluminum hydride in toluene added dropwise over 20 min. Theresulting mixture was then stirred at −78° C. for 3 h. The reactionmixture was quenched by the careful addition of methanol (5 mL) addeddropwise over 15 min, followed by 1N hydrochloric acid (50 mL) addeddropwise over 15 min. The cooling bath was then removed and anadditional 150 mL of 1N hydrochloric acid was added over 20 min. Themixture was then stirred at 22° C. for 2 h and diluted withdichloromethane (400 mL). The organic phase was collected and theaqueous phase (pH˜1) was extracted with dichloromethane (3×50 mL). Thecombined organic extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residual oil wasdiluted with tetrahydrofuran (70 mL), treated with 10 mL of 0.1Nhydrochloric acid and stirred at 20° C. for 2 h. The reaction mixturewas diluted with ethyl acetate (300 mL), washed with brine, dried overanhydrous magnesium sulfate, evaporated in vacuo to give a clear oil.Chromatography on silica gel (4×13 cm, elution toluene) gave 4.08 g (73%yield) of the title aldehyde as a clear oil which solidified onstanding. LC (Method C): 2.237 min. HRMS(ESI) calcd for C₁₅H₁₅O₄ [M+H]⁺m/z 259.0965, found 259.1153. ¹H NMR (CDCl₃, 600 MHz) δ 3.80 (s, 3H),5.07 (s, 2H), 5.97 (d, J=2.1 Hz, 1H), 6.01 (d, J=2.1 Hz, 1H), 7.3-7.4(m, 5 H, 10.15 (s, 1H), 12.49 (s, 1H).

1D. 1-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)ethanone

A solution of 2-(benzyloxy)-6-hydroxy-4-methoxybenzaldehyde (Example 1C,3.46 g, 13.4 mmol) in N,N-dimethylformamide (50 mL) was treated withpowdered anhydrous cesium carbonate (4.58 g, 14.05 mmol) added all atonce. The resulting mixture was stirred in vacuo for 10 min. and thenflushed with nitrogen. The reaction flask was placed in a water bath(22° C.) and treated with chloroacetone (1.74 g, 18.7 mmol) addeddropwise over 5 min. The resulting mixture was then stirred at 22° C.for 18 h (no starting aldehyde left by tlc and formation of theintermediate alkylated aldehyde). The solid was filtered and washed withN,N-dimethylformamide. The filtrate was evaporated in vacuo and theresidual oil was diluted with ethyl acetate (300 mL), washed with cold0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. Afterdrying over anhydrous magnesium sulfate, evaporation of the solvent gavea thick syrup. This syrup was diluted with tetrahydrofuran (50 mL) andethyl acetate (50 mL), treated p-toluenesulfonic acid monohydrate (0.2g) and stirred at 20° C. for 1 h (tic indicated complete cyclization ofthe intermediate alkylated aldehyde to the benzofuran). The reactionmixture was diluted with ethyl acetate (300 mL), washed with saturatedsodium bicarbonate and brine. After drying over anhydrous magnesiumsulfate, evaporation of the solvent gave a thick syrup. Chromatographyon silica gel (4×12 cm, elution toluene-ethyl acetate 2-4%) gave 3.51 g(88% yield) of the title benzofuran as a yellow solid. Recrystallizationfrom ethyl acetate (10 mL) and hexane (20 mL) gave the title material aslarge yellow prisms (3.15 g). LC (Method D): 2.148 min. HRMS(ESI) calcdfor C₁₈H₁₇O₄ [M+H]⁺ m/z 297.1121, found 297.1092. ¹H NMR (CDCl₃, 600MHz) δ 2.51 (s, 3H), 3.82 (s, 3H), 5.13 (s, 2H), 6.37 (d, J=1.77 Hz,1H), 6.63 (broad s, 1H), 7.34 (broad t, 1H), 7.39 (broad t, 2H), 7.44(broad d, 2H), 7.55 (d, J=0.7 Hz,1H).

1E. 1-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone

A 250-mL, three-necked flask is equipped with a magnetic stirring barand purged with a nitrogen atmosphere was charged with anhydroustetrahydrofuran (25 mL) followed by 9.3 mL (9.3 mmol) of a 1M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran. The mixture wascooled to −78° C. and treated with a solution of1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)ethanone (Example 1D, 2.40 g,8.1 mmole) in tetrahydrofuran (20 mL) added dropwise over 10 min. Theresulting mixture was then stirred at −78° C. for 45 min. Thenchlorotrimethylsilane (1.18 mL, 9.31 mmol) was added dropwise over 5 minand the resulting solution was stirred at −78° C. for another 20 min.The cooling bath was then removed and the mixture is allowed to warm toroom temperature over 30 min. The reaction mixture was then quenched byaddition to a cold solution of ethyl acetate (200 mL), saturated sodiumbicarbonate (30 mL) and ice. The organic phase was rapidly dried overanhydrous magnesium sulfate (magnetic stirring) and evaporated in vacuoto give the silyl enol ether as an oil which is co-evaporated withtoluene (20 mL). The silyl enol ether was then dissolved in drytetrahydrofuran (40 mL), cooled to −20° C. and treated with solid sodiumbicarbonate (0.10 g) followed by N-bromosuccinimide (1.44 g, 8.1 mmol)added in small portions over 15 min. The reaction mixture was allowed towarm to 0° C. over 2h and then quenched by addition of ethyl acetate(300 mL) and saturated sodium bicarbonate. The organic phase was washedwith brine, dried over anhydrous magnesium sulfate and evaporated togive an orange oil. Chromatography on silica gel (4×12 cm, elutiontoluene-ethyl acetate 0-5%) gave 2.62 g (86% yield) of the titlebromomethylketone as a yellow solid. Recrystallization from ethylacetate (10 mL) and hexane (20 mL) gave yellow prisms (2.30 g). LC(Method E): 1.977 min. HRMS(ESI) calcd for C₁₈H₁₆BrO₄ [M+H]⁺ m/z375.0226, found 375.0277. ¹H NMR (CDCl₃, 600 MHz) δ 3.84 (s, 3H), 4.33(s, 2H), 5.14 (s, 2H), 6.38 (d, J=1.76 Hz, 1H), 6.64 (broad s, 1H), 7.35(broad t, 1H), 7.40 (broad t, 2H), 7.44 (broad d, 2H), 7.70 (s, 1H).

1EE. 1-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-chloroethanone

Benzyltrimethylammonium dichloroiodate (117 g, 169 mmol) was added to asolution of 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)ethanone (Example1D, 50 g, 170 mmol) in THF (500 mL) in a 1 L multineck round bottomflask under nitrogen atmosphere. The reaction mixture was stirred at RTfor 6 h, cooled to 0° C. and quenched with 10% NaHCO₃ solution. Theorganic layer was washed with 1 M sodium thiosulphate solution, water,and brine, dried over Na₂SO₄, and concentrated in vacuo (bathtemperature <45° C.). The residue was triturated with 5% EtOAc in pet.ether and dried to obtain the title chloromethylketone as a pale yellowsolid (48 g, 130 mmol, 78%). ¹H NMR (300 MHz, DMSO-d₆) δ 3.84-3.82 (d,J=4.5 Hz, 3H) 4.98 (s, 2H), 5.27 (s, 2H), 6.62-6.61 (d, J=1.8 Hz, 1H),6.92-6.93 (m, 1H), 7.54-7.36 (m, 5H), 8.10-8.09 (d, J=3 Hz, 1H); MS m/z:[M+H]⁺ 331.0.

1F.6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole

A mixture of 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone(Example 1E, 3.00 g, 8.0 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine(1.65 g, 9.16 mmol) in isopropanol (100 mL) was heated in a pressureflask equipped with a magnetic stirring bar at 78-80° C. for 18 h(homogeneous after 20 min and then formation of a precipitate after 2H.The cooled mixture is then transferred into five 20 mL microwave vialsand then heated in a microwave apparatus to 150° C. for 30 min. Eachvial was then diluted with dichloromethane (250 mL) washed withsaturated sodium bicarbonate (25 mL) and brine (25 mL), dried overanhydrous magnesium sulfate. The fractions were combined andconcentrated in vacuo. Chromatography of the orange-brown residual solidon silica gel (4×10 cm, slow elution with dichloromethane due to poorsolubility) gave 2.96 g of the title imidazothiadiazole contaminatedwith some 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)ethanone. The solidmaterial was triturated with ethyl acetate (20 mL), filtered, washedwith ethyl acetate (10 ml) and dried in vacuo to give 2.34 g (64% yield)of pure title imidazothiadiazole as an off white solid which is used assuch for the next step. LC (Method E): 2.188 min. HRMS(ESI) calcd forC₂₀H₁₅BrN₃O₃S [M+H]⁺ m/z 456.00175, found 456.00397. ¹H NMR (CDCl₃, 600MHz) δ 3.82 (s, 3H), 5.16 (s, 2H), 6.38 (d, J=1.67 Hz, 1H), 6.66 (broads, 1H), 7.15 (s, 1H), 7.31 (broad t, 1H), 7.38 (broad t, 2H), 7.45(broad d, 2H), 8.02 (s, 1H).

Alternatively, Example 1F,6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole,was prepared as follows:

A 1000-mL, three-necked flask equipped with a magnetic stirring bar andpurged with a nitrogen atmosphere was charged with dry NMP (200 mL)followed by 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-chloroethanone(Example 1EE, 50 g, 150 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (27.2g, 151 mmol). The resulting mixture was stirred at 80° C. for 8 h. TLC(8:2 dichloromethane/pet. ether) and LC/MS showed intermediateuncyclized material (m/z 476) and the reaction mixture was stirred at120° C. for 3 h. The reaction mixture was cooled to RT, quenched withwater and extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thethick brown residue was purified by silica gel chromatography (0 to 100%dichloromethane in pet. ether) to give a brown solid. This material wastriturated with EtOAc and dried to obtain the title imidazothiadiazole(24 g, 50 mmol, 33%) as a light brown solid. (See the procedure setforth above for analytical data).

1G.6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A solution of6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole(Example 1F, 2.30 g, 5.04 mmol) in a mixture of dichloromethane (180 mL)and methanol (45 mL) was treated at 22° C. with 4.2 mL of a 25 wt. %solution of sodium methoxide in methanol (0.2 mmol) added in oneportion. More methanol (45 mL) was added and the mixture was stirred for1 h. The reaction mixture was quenched by the addition of 25 mL of 1Nhydrochloric acid followed by 20 ml of saturated sodium bicarbonate. Thesolvent was evaporated under reduced pressure and the residue wasdiluted with dichloromethane (400 mL), washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. Chromatography ofthe residue on silica gel (3×10 cm, elution with dichloromethane-ethylacetate 0-4%) gave 1.70 g (83% yield) of the title compound as a whitesolid. This material was recrystallized from ethyl acetate (30 mL pergram, 80% recovery) to give white needles. LC (Method D): 2.293 min.HRMS(ESI) calcd for C₂₁H₁₈N₃O₄S [M+H]⁺ m/z 408.1013, found 408.1024. ¹HNMR (CDCl₃, 600 MHz) δ 3.81 (s, 3H), 4.18 (s, 3H), 5.16 (s, 2H), 6.37(d, J=1.75 Hz, 1H), 6.67 (broad s, 1H), 7.07 (s, 1H), 7.31 (broad t,1H), 7.37 (broad t, 2H), 7.45 (broad d, 2H), 7.81 (s, 1H).

1H.6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol

A mixture of6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(Example 1G, 1.250 g, 3.06 mmol) and pentamethylbenzene (3.17 g, 21.4mmol) in dichloromethane (200 mL) was cooled to −78° C. under a nitrogenatmosphere and then treated immediately (to avoid crystallization) with8 mL (8 mmol) of a 1 M solution of boron trichloride in dichloromethaneadded dropwise over 3 min. The resulting mixture was stirred at −78° C.for 1 h. The reaction mixture was then quenched by the addition of asolution of sodium bicarbonate (6 g) in water (100 mL) added in oneportion. The cooling bath was removed and the resulting mixture wasstirred at room temperature for 1 h. The solid formed was filtered,washed successively with water (50 m) and dichloromethane (50 mL). Thefilter cake was allowed to soak with anhydrous ethanol (15 ml) and thensucked dry. The white solid obtained was then dried under vacuum for 24h to give 0.788 g (80% yield) of pure title material (>95% by hplc). Thecombined filtrate and washings were diluted with dichloromethane (600mL) and stirred in a warm water bath till the organic phase was clearwith no apparent solid in suspension. The organic phase was collected,dried over anhydrous magnesium sulfate and rapidly filtered while stillwarm. The filtrate was evaporated and the residue (product andpentamethylbenzene) was triturated with toluene (20 mL), the solidcollected and washed with toluene (20 mL) to give 0.186 g (19% yield,99% combined yield) of title material as a tan solid (>95% by hplc). LC(Method E): 1.444 min. HRMS(ESI) calcd for C₁₄H₁₂N₃O₄S [M+H]⁺ m/z318.0543, found 318.0578. ¹H NMR (DMSO-d₆, 600 MHz) δ 3.71 (s, 3H), 4.16(s, 3H), 6.21 (d, J=1.87 Hz, 1H), 6.61 (broad s, 1H), 6.95 (s, 1H), 8.29(s, 1H), 9.96 (s, 1H).

Example 12-Methoxy-6-(6-methoxy-4-((2-methylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.100 g, 0.315 mmol) and triphenylphosphine (0.123 g, 0.47mmol) was maintained under vacuum for 10 minutes. The mixture wasflushed with nitrogen and then charged with dry THF (8 mL) and(2-methylthiazol-4-yl)methanol (Example 1A, 0.049 g, 0.38 mmol). Themixture was warmed to 50° C. and sonicated for 5 minutes. The cooledmixture was treated with a solution of DIAD (0.096 g, 0.47 mmol) in dryTHF (2 mL) added in three portions dropwise over 20 minutes. The mixturewas homogeneous after 40 min. and was stirred at 22° C. for 6 h. Thereaction mixture was diluted with dichloromethane (250 mL), washed withsat. sodium bicarbonate, brine and dried over anhydrous MgSO₄.Evaporation gave a semi-solid residue which was purified bychromatography on silica gel (2.5×10 cm, dichloromethane/EtOAc 8:2) toprovide the title material (0.103 g, 76%) as white cubes. LC (Method A):2.224 min. HRMS(ESI) calcd for C₁₉H₁₇N₄O₄S₂ [M+H]⁺ m/z 429.0686, found429.0605. ¹H NMR (CDCl₃, 600 MHz) δ 7.82 (s, 1H), 7.17 (s, 1H), 7.06 (s,1H), 6.67 (m, 1H), 6.39 (d, J=1.89 Hz, 1H), 5.25 (d, J=0.9 Hz, 2H), 4.18(s, 3H), 3.82 (s, 3H), 2.72 (s, 3H).

Example 22-Methoxy-6-(6-methoxy-4-((2-(trifluoromethyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

2A. Ethyl 2-(trifluoromethyl)thiazole-4-carboxylate

A mixture of 2,2,2-trifluoroacetamide (7.12 g, 63 mmol) and Lawesson'sreagent (15.3 g, 37.8 mmol) in THF (60 mL) was heated at reflux for 18hours. The reaction was then cooled down to RT and treated with ethylbromopyruvate (8.0 mL, 63 mmol). The reaction was stirred at reflux foran additional 18 hours, then concentrated under vacuum and diluted withethyl acetate. This mixture was washed with water (1×) and brine (1×),dried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue was purified by silica gel chromatography (8×11 cm, toluene,then second time with 120 g silica gel, hexane/ethyl acetate) to givethe title material (4.47 g, 32%) as a pale yellow solid. ¹H NMR (CDCl₃,400 MHz) δ 8.37 (s, 1H), 4.45 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 1H).

2B. (2-(Trifluoromethyl)thiazol-4-yl)methanol

Ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (Example 2A, 1.50 g,6.66 mmol) was reacted as described in Example 1A and afforded thedesired title material (0.95 g, 78%) as a clear oil after distillation(b.p.: 55-65° C./0.2 ton). ¹H NMR (CDCl₃, 400 MHz) δ 7.47 (s, 1H), 4.85(s, 2H), 2.25 (br s, 1H).

Example 22-Methoxy-6-(6-methoxy-4-((2-(trifluoromethyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.100 g, 0.315 mmol) and(2-(trifluoromethyl)thiazol-4-yl)methanol (Example 2B, 0.075 g, 0.409mmol) were reacted as described in Example 1 and afforded the titlematerial (0.070, 46%) after crystallization in AcOEt. LC (Method B):2.448 min. HRMS(ESI) calcd for C₁₉H₁₄F₃N₄O₄S₂ [M+H]⁺ m/z 483.0403, found483.0411. ¹H NMR (CDCl₃, 600 MHz) δ 7.82 (s, 1H), 7.17 (s, 1H), 7.06 (s,1H), 6.67 (m, 1H), 6.39 (d, J=1.89 Hz, 1H), 5.25 (d, J=0.9 Hz, 2H), 4.18(s, 3H), 3.82 (s, 3H), 2.72 (s, 3H).

Example 32-Methoxy-6-(6-methoxy-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

3A. Methyl 2-phenylthiazole-4-carboxylate

A solution of benzothioamide (4.0 g, 29.2 mmol) in THF (80 mL) wastreated dropwise with methyl bromopyruvate (7.6 g, 39 mmol) and heatedat reflux for 18 hours. The reaction was then concentrated under vacuum,diluted with ethyl acetate, washed with water (1×), brine (1×) and driedover anhydrous magnesium sulfate. The residue obtained afterconcentration was purified by silica gel chromatography (4.5×11 cm, 20%AcOEt/toluene), followed by a second purification with 20% AcOEt/hexane.The title material was obtained after concentration as a yellow oil(5.25, 77%). ¹H NMR (CDCl₃, 400 MHz): 8.14 (s, 1H) 8.00 (m, 2H)7.46-7.42 (m, 3H) 4.43 (q, J=7.0 Hz, 2H) 1.42 (t, J=7.3 Hz, 3H).

3B. (2-Phenylthiazol-4-yl)methanol

In a 250 mL round-bottom flask, methyl 2-phenylthiazole-4-carboxylate(Example 3A, 1.50 g, 6.43 mmol) was dissolved in ethyl ether (40 mL).The solution was cooled down to −78° C. and treated with lithiumaluminum hydride (0.75 g, 19.76 mmol) portionwise over 20 minutes. Thereaction was stirred at −78° C. for 3.5 hours, then treated with 20 mLof a saturated solution of Na₂SO₄. The reaction was allowed to reach RTand was diluted with ethyl acetate, washed with HCl 1N (1×), brine (1×),dried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue was purified by silica gel chromatography (3×12 cm, 30% ethylacetate/dichloromethane) to give a pale yellow oil (1.06 g) which wasthen distilled (bulb to bulb, bp: 110-120° C./0.2 torr) and provided thetitle material (0.88 g, 72%) as a clear oil. ¹H NMR (CDCl₃, 400 MHz):7.95-7.90 (m, 2H) 7.45-7.40 (m, 3H) 7.16 (s, 1H) 4.82 (s, 2H) 2.34 (brs, 1H).

Example 32-Methoxy-6-(6-methoxy-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.800 g, 2.52 mmol), triphenylphosphine (0.992 g, 3.78mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.555 g, 2.90mmol) in a 200 mL flask fitted with an addition funnel was maintainedunder vacuum for ten minutes. The mixture was then flushed with nitrogenand charged with dry tetrahydrofuran (60 mL, distilled over lithiumaluminum hydride). The solution was warmed to ˜50° C. and then sonicatedfor 5 min. The cooled heterogeneous mixture was then treated at 22° C.with a solution of diisopropyl azodicarboxylate (0.663 g, 3.28 mmol) intetrahydrofuran (15 mL), added dropwise over 2.5 h. The reaction washomogeneous (pale yellow) at the end of the addition. The mixture wasthen stirred for another 2.5 h (total 5H. The reaction mixture was thendiluted with dichloromethane (400 mL), washed with saturated sodiumbicarbonate (20 mL), brine and dried (anhydrous magnesium sulfate).Evaporation gave a white solid which was chromatographed on silica gel(3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3). Thefractions were collected and evaporated to give the desired compound(1.40 g) as a white solid, contaminated with hydrazide by tlc.Crystallization in ethyl acetate (40 mL) gave the pure title material(0.838 g, 68%) as a white solid. The mother liquors (0.475 g) werechromatographed on silica gel (3×12 cm, elution dichloromethane-ethylacetate 98.5:1.5 to 97:3) to give after crystallization from ethylacetate (30 mL) to provide additional desired compound (0.160 g, 13%,total 81%) as a white solid. LC (Method C): 2.480 min. HRMS(ESI) calcdfor C₂₄H₁₉N₄O₄S₂ [M+H]⁺ m/z 491.0842, found 491.0865. ¹H NMR (CDCl₃, 400MHz) 3.85 (s, 3H) 4.21 (s, 3H) 5.33-5.55 (m, 2H) 6.48 (d, J=1.96 Hz, 1H)6.72 (dd, J=1.96, 0.78 Hz, 1H) 7.12 (s, 1H) 7.36-7.39 (m, 1H) 7.41-7.50(m, 3H) 7.86 (s, 1H) 7.95-8.02 (m, 2H).

Example 42-Methoxy-6-(6-methoxy-4-((4-phenylthiazol-2-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

4A. Ethyl 2-amino-2-thioxoacetate

A solution of ethyl 2-amino-2-oxoacetate (5.00 g, 42.7 mmol) intetrahydrofuran (150 mL) was treated with powdered (mortar and pestle)Lawesson's Reagent (9.50 g, 23.49 mmol) and the resulting orange clearsolution was heated under reflux (bath temperature 85° C.) for 4 h (TLCproduct with higher Rf formed with some starting material left). Thecooled mixture was concentrated under reduced pressure and the residuewas diluted with ethyl acetate (400 mL) washed with saturated sodiumbicarbonate, brine and dried over anhydrous magnesium sulfate.Evaporation gave an orange solid which was chromatographed on silica gel(3×10 cm, elution toluene-ethyl acetate 9:1) and provided the titlematerial (3.189 g, 56%) of a yellow solid. LC (Method C): 0.816 min. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 1.41 (t, J=7.0 Hz, 3H), 4.38 (q, J=7.0 Hz,2H), 7.69 (br s, 1H) 8.24 (br s, 1H).

4B. Ethyl 4-phenylthiazole-2-carboxylate

A mixture of 2-bromo-1-phenylethanone (1.790 g, 8.99 mmol) and ethyl2-amino-2-thioxoacetate (Example 4A, 1.20 g, 9.01 mmol) in benzene (80mL) and ethanol (10 mL) was stirred at room temperature for 18 h. Themixture was heated at 80° C. for 1 h. The solvent was evaporated underreduced pressure and the residue was partitioned between ethyl acetate(300 mL) and saturated aqueous sodium bicarbonate (100 mL). The organicphase was washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residual clear oil was chromatographed onsilica gel (4×10 cm, elution toluene-ethyl acetate 0-2-4%) and gave ayellow oil (1.588 g). This was distilled in vacuo (bp: 105-115° C./0.1torr, bulb to bulb distillation, air bath temperature) to provide thetitle material (1.409 g, 67%) as a pale yellow syrup which solidified toan almost colorless solid upon standing. LC (Method C): 2.009 min.HRMS(ESI) calcd for C₁₂H₁₂NO₂S [M+H]⁺ m/z 234.0583, found 234.0597. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 1.48 (t, J=7.2 Hz, 3H), 4.52 (q, J=7.2 Hz,2H), 7.35-7.49 (m, 3H), 7.75 (s, 1H), 7.93-8.00 (m, 2H).

4C. 2-(Hydroxymethyl)-4-phenylthiazole

A solution of ethyl 4-phenylthiazole-2-carboxylate (Example 4B, 1.300 g,5.57 mmol) in diethyl ether (60 mL) in a 500 mL flask under a nitrogenatmosphere was cooled to −40° C. (dry ice-water-calcium chloride bath)and treated with solid LiAlH₄ (0.40 g, 10.54 mmol) added all at once.The mixture was stirred at −40° C. over 2.5 h. The reaction was quenchedby dropwise addition of ethyl acetate (1 mL), water (0.4 mL) followed by15% aqueous sodium hydroxide (0.4 mL) and water (1.2 mL). The bath wasthen removed and the mixture was stirred at room temperature for 50 min.The solid formed was filtered and washed with ether (50 mL). Thecombined filtrate and washing was washed with brine (20 mL) and driedover anhydrous magnesium sulfate. Evaporation gave a yellow oil whichwas purified by silica gel chromatography (2.5×8 cm, elutiontoluene-ethyl acetate 9:1, 8:2 to 7:3). The resulting light yellow oil(0.931 g) was then distilled in vacuo (bp: 105-110° C./0.1 torr, bulb tobulb, air bath temperature) to provide the title material (0.918 g, 86%)of a colorless syrup. LC (Method C): 1.672 min. HRMS(ESI) calcd forC₁₀H₁₀NOS [M+H]⁺ m/z 192.0478, found 192.0508. ¹H NMR (CDCl₃, 400 MHz) δppm: 2.90 (br t, 1H), 5.02 (d, J=4.30 Hz, 2H), 7.31-7.38 (m, 1H),7.39-7.45 (m, 2H), 7.46 (d, J=0.8 Hz, 1H), 7.85-7.92 (m, 2H).

4D. 2-(Bromomethyl)-4-phenylthiazole

A solution of (4-phenylthiazol-2-yl)methanol (Example 4C, 0.530 g, 2.77mmol) in dichloromethane (10 mL) was cooled to 0° C. (ice bath) andtreated with PBr₃ (0.118 mL, 1.247 mmol) added dropwise over 2 min. Aheavy white gum was immediately formed. After 10 min, the bath wasremoved and the solution was stirred at 22° C. for 4 h. The reactionmixture was quenched with ice (˜10 g) and poured into a mixture of ethylacetate (150 mL) and saturated sodium bicarbonate (50 mL). The organicphase was washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The solid residue was chromatographed on silicagel (2.5×6 cm, elution toluene) to give the title material (0.561 g,80%) as a light yellow oil which solidified in the fridge to a paleyellow solid. LC (Method C): 2.062 min. HRMS(ESI) calcd for C₁₀H₉BrNS[M+H]⁺ m/z 253.9634, found 253.9655. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.81(s, 2H), 7.34-7.39 (m, 1H), 7.41-7.47 (m, 2H), 7.52 (s, 1H), 7.86-7.92(m, 2H).

Example 42-Methoxy-6-(6-methoxy-4-((4-phenylthiazol-2-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.080 g, 0.252 mmol) and 2-(bromomethyl)-4-phenylthiazole(0.128 g, 0.504 mmol) in N,N-Dimethylformamide (3 mL) was maintainedunder vacuum (10 mbar) for 5 minutes. The flask was then flushed withnitrogen and anhydrous freshly powdered (mortar and pestle) potassiumcarbonate (0.105 g, 0.756 mmol) was added all at once. The resultingmixture was stirred at room temperature with a few short sonicationperiods (˜1 min) for 1 hour. The heterogeneous mixture became almosthomogeneous (except the potassium carbonate) after 10 min and started toprecipitate again to a cream solid. The reaction mixture was quenchedwith 1N hydrochloric acid (2 mL) and then partitioned betweendichloromethane (150 mL) and saturated sodium bicarbonate (20 mL). Theorganic phase was washed with brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The solid pale yellow residue waschromatographed on silica gel (2.5×6 cm, elution dichloromethane-ethylacetate 0-2-5%) to give the title material (0.116 g, 94%) as a paleyellow solid. Crystallization in ethyl acetate (12 mL) provided thetitle material (0.086 g) as a pale yellow solid. LC (Method C): 2.474min. HRMS(ESI) calcd for C₂₄H₁₉N₄O₄S₂ [M+H]⁺ m/z 491.0842, found491.0864. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 3.86 (s, 3H), 4.22 (s, 3H),5.54 (s, 2H), 6.48 (d, J=1.96 Hz, 1H), 6.75 (broad d, 1H), 7.15 (s, 1H),7.32-7.39 (m, 1H), 7.41-7.49 (m, 2H), 7.53 (s, 1H), 7.87 (s, 1H),7.90-7.95 (m, 2H).

Example 54-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)morpholine

5A. Methyl 2-morpholinothiazole-4-carboxylate

A solution of methyl 2-bromothiazole-4-carboxylate (0.20 g, 0.901 mmol)in THF (10 mL) was treated with morpholine (0.17 mL, 1.94 mmol) andrefluxed for 18 h. The reaction was then diluted with ethyl acetate andwashed with sat. NaHCO₃ (1×), brine (1×) and dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was purifiedby silica gel chromatography (2.5×10 cm, 50% AcOEt/CH₂Cl₂) to give thetitle material (0.192 g, 92%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 7.44 (s, 1H) 3.82 (s, 3H) 3.75 (m, 4H) 3.45 (m, 4H).

5B. (2-Morpholinothiazol-4-yl)methanol

A solution of methyl 2-morpholinothiazole-4-carboxylate (0.76 g, 3.33mmol) in ethyl ether (20 mL) was treated portion wise over 10 min. withlithium aluminum hydride (0.38 g, 10.01 mmol). The mixture was stirredat −78° C. for 4 hours, then slowly treated with ethyl acetate (10 mL)and sat. Na₂SO₄ (20 mL). The mixture was allowed to warm up to RT,diluted with ethyl acetate, washed with sat. NaHCO₃ (1×), brine (1×),dried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue was purified on silica gel chromatography (3×10 cm, 25%AcOEt/CH₂Cl₂ to 100% AcOEt) to give the title material as a beige solid(0.458 g) which was then distilled (bulb to bulb, 135-145° C./0.2 torr)and afforded the desired product (0.455 g, 68%) as a white solid. LC(Method F): 0.873 min. HRMS(ESI) calcd for C₈H₁₃N₂O₂S [M+H]⁺ m/z 201.07.found 201.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 6.43 (s, 1H) 4.53 (d, J=3.9Hz, 2H) 3.79 (m, 4H) 3.44 (m, 4H) 2.17 (s, 1H).

Example 54-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)morpholine

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.10 g, 0.315 mmol), triphenylphosphine (0.124 g, 0.473mmol) and (2-morpholinothiazol-4-yl)methanol (Example 5B, 0.086 g, 0.429mmol) were added in a 25 mL round-bottom flask and purged under vacuumand nitrogen. Tetrahydrofuran (8 mL) was then added and the mixture wastreated with DIAD (0.083 g, 0.410 mmol) in tetrahydrofuran (10 mL). Themixture was stirred at 22° C. for 1 hour and diluted with ethyl acetate.This was washed with sat. NaHCO₃ (1×) and brine (1×), dried overanhydrous magnesium sulfate, filtered and concentrated. The residue waspurified on silica gel column chromatography (2.5×10 cm, 40% ethylacetate in CH₂Cl₂) and the residue obtained after concentration wascrystallized in ethyl acetate to give the title material as crystals(0.083 g, 53%) and as an amorphous impure solid from the mother liquor(0.169 g). LC (Method F): 2.466 min. HRMS(ESI) calcd for C₂₂H₂₂N₅O₅S₂[M+H]⁺ m/z 500.1057, found 500.1075. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.82(s, 1H) 7.07 (s, 1H) 6.67 (d, J=2 Hz, 1H) 6.62 (s, 1H) 6.40 (d, J=1.5Hz, 1H) 5.10 (s, 2H) 4.19 (s, 3H) 3.82 (s, 3H) 3.81 (m, 4H) 3.46 (m,4H).

Example 62-Methoxy-6-(6-methoxy-4-((2-((2-methoxyethoxy)methyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

6A. 2-(2-Methoxyethoxy)acetamide

A solution of 2-(2-methoxyethoxy)acetic acid (5.0 g, 37.3 mmol) inCH₂Cl₂ (50 mL) was treated with oxalyl chloride (9.5 mL, 109 mmol) andDMF (2 drops) and the reaction was stirred for 3 hours. Afterevaporation under vacuum, the residue was co-evaporated with CH₂Cl₂ (2×)and then dissolved in THF (10 mL) and treated dropwise with a mixture ofammonium hydroxide (12 mL), THF (25 mL) and water (10 mL) for 5 min. Thereaction was then stirred at 0-5° C. for 30 min. then at 22° C. for 1 h.The reaction was diluted with CH₂Cl₂, washed with water (1×), HCl 1N(1×), sat. NaHCO₃ (1×) and brine (1×), dried over anhydrous magnesiumsulfate, filtered and concentrated. As the product appeared to besoluble in water, the aqueous phase was evaporated under vacuum andextracted with CH₂Cl₂ (5×200 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated to give the title material (3.59 g,72%) as an oil which solidified. This was distilled (bulb to bulb,105-115° C./0.2 ton) to provide the pure desired product (3.39 g) as aclear oil which solidified as a white solid. ¹H NMR (CDCl₃, 400 MHz) δppm: 6.93 (very broad s, 1H), 5.43 (very broad s, 1H), 3.99 (s, 2H),3.66-3.70 (m, 2H), 3.53-3.56 (m, 2H), 3.39 (s, 3H).

6B. 2-(2-Methoxyethoxy)ethanethioamide

A solution of 2-(2-methoxyethoxy)acetamide (Example 6A, 3.39 g, 25.5mmol) in THF (40 mL) was treated with Lawesson's reagent (6.55 g, 16.19mmol) and the reaction was refluxed for 18 hours. The reaction was thenallowed to cool down to RT and was concentrated under vacuum, dilutedwith ethyl acetate, washed with sat. NaHCO₃ (1×) and brine (1×). Theaqueous phases were extracted with ethyl acetate (2×200 mL) and theorganic extracts were dried over anhydrous magnesium sulfate, filteredand concentrated. The residue was purified by silica gel chromatography(3.5×11 cm, 30% AcOEt/CH₂Cl₂) to give the title material (3.26 g, 86%)as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.58 (very broad s, 1H),7.50 (very broad s, 1H), 4.36 (s, 2H), 3.66-3.69 (m, 2H), 3.53-3.56 (m,2H), 3.39 (s, 3H).

6C. Ethyl 2-((2-methoxyethoxy)methyl)thiazole-4-carboxylate

To a solution of 2-(2-methoxyethoxy)ethanethioamide (Example 6B, 3.26 g,21.85 mmol) in ethanol (60 mL) was added dropwise ethylbromopyruvate(3.7 mL, 29.5 mmol) and the mixture was refluxed for 18 hours. Thereaction was then concentrated under vacuum, diluted with ethyl acetate,washed with water (1×), brine (1×), dried over anhydrous magnesiumsulfate, filtered and concentrated. The residue was purified by silicagel column chromatography (3.5×10 cm, 30% ethyl acetate/CH₂Cl₂) to givethe title material (4.36 g, 81%) as an oil. LC (Method F): 1.791 min. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 8.16 (s, 1H), 4.87 (s, 2H), 4.41 (q, J=7.10Hz, 2H), 3.74-3.77 (m, 2H), 3.57-3.60 (m, 2H), 3.39 (s, 3H), 1.39 (t,J=7.10 Hz, 3H).

6D. (2-((2-Methoxyethoxy)methyl)thiazol-4-yl)methanol

To a solution of ethyl 2-((2-methoxyethoxy)methyl)thiazole-4-carboxylate(Example 6C, 2.27 g, 9.25 mmol) in ether (50 mL) was added portion wiselithium aluminum hydride (1.06 g, 27.9 mmol) over 10 min. at −78° C. Thereaction was then stirred at −78° C. for 1 hour. Ethyl acetate (10 mL)was then added to the reaction followed by water (20 mL) and thereaction was allowed to reach RT. The mixture was then diluted withethyl acetate, washed with HCl 1N (1×) and brine (1×). The combinedaqueous phases were extracted with ethyl acetate (2×300 mL), dried overanhydrous magnesium sulfate, filtered and concentrated. The residue waspurified by silica gel chromatography (3.5×10 cm, ethyl acetate) to givethe title material (0.357 g, 19%) as a brown oil. LC (Method F): 1.791min. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.16 (s, 1H), 4.82 (s, 2H), 4.74(broad s, 2H), 3.7-3.75 (m, 2H), 3.54-3.61 (m, 2H), 3.38 (s, 3H), 2.28(broad s, 1H).

6E. 4-(Bromomethyl)-2-((2-methoxyethoxy)methyl)thiazole

A solution of (2-((2-methoxyethoxy)methyl)thiazol-4-yl)methanol (0.35 g,1.72 mmol) in ether (15 mL) was treated with PBr₃ (0.1 mL, 1.06 mmol) atRT. There is formation of a precipitate. The reaction was stirred at RTfor 18 hours, then diluted with ethyl acetate and washed with sat.NaHCO₃ (1×) and brine (1×), dried over anhydrous magnesium sulfate,filtered and concentrated. The residue was purified by silica gelchromatography (3×10 cm, 20% ethyl acetate/CH₂Cl₂) to give the titlematerial (0.233 g, 51%) as a clear oil. ¹H NMR (CDCl₃, 400 MHz) δ ppm:7.27 (s, 1H), 4.83 (s, 2H), 4.55 (s, 2H), 3.73-3.76 (m, 2H), 3.57-3.60(m, 2H), 3.39 (s, 3H).

Example 62-Methoxy-6-(6-methoxy-4-((2-((2-methoxyethoxy)methyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.10 g, 0.315 mmol) and4-(bromomethyl)-2-((2-methoxyethoxy)methyl)thiazole (Example 6E, 0.10 g,0.376 mmol) in DMF (5 mL) was purged under vacuum and nitrogen for 10minutes. The mixture was then treated with potassium carbonate (0.10 g,0.724 mmol) and the reaction was stirred at RT for 2.5 hours. Thereaction was then diluted with dichloromethane, washed with water (1×),brine (1×), dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(2.5×10 cm, 50% ethyl acetate/CH₂Cl₂) to give the title material whichwas crystallized in ethyl acetate and provided the desired titlematerial (0.055 g, 35%) along with non-crystallized material (9 mgs,6%). LC (Method F): 2.476 min. HRMS(ESI) calcd for C₂₂H₂₃N₄O₆S₂ [M+H]⁺m/z 503.1054, found 503.1066. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.82 (s,1H), 7.35 (s, 1H), 7.05 (s, 1H), 6.68 (broad s, 1H), 6.39 (d, J=1.9 Hz,1H), 5.28 (s, 2H), 4.86 (s, 2H), 4.19 (s, 3H), 3.82 (s, 3H), 3.74-3.77(m, 2H), 3.58-3.61 (m, 2H), 3.39 (s, 3H).

Example 72-Methoxy-6-(6-methoxy-4-((5-phenyl-1,2,4-thiadiazol-3-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

7A. Ethyl 5-phenyl-1,2,4-thiadiazole-3-carboxylate

A mixture of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate (U.S.Publication No. 2005/0096362) (1.5 g, 8.56 mmol) and benzonitrile (4.37ml, 42.8 mmol) in 1,2-dichrlotobenzene (15.42 ml, 137 mmol) was heatedto 160° C. for 4 days. The reaction was then cooled down to RT and thesolvent was evaporated by heated the reaction at 75° C. at maximumvacuum. The residue was purified on silica gel chromatography (100%CH₂Cl₂ to 3% EtOAc in CH₂Cl₂) to provide the title material (0.064 g,3%). LC (Method B): 2.021 min. HRMS(ESI) calcd for C₁₁H₁₁N₂O₂S [M+H]⁺m/z 235.0541, found 235. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.01-8.09 (m,1H), 7.49-7.59 (m, 2H), 4.56 (q, J=7.17 Hz, 1H), 1.50 (t, J=7.24 Hz,1H).

7B. (5-Phenyl-1,2,4-thiadiazol-3-yl)methanol

To a solution of ethyl 5-phenyl-1,2,4-thiadiazole-3-carboxylate (Example7A, 230 mg, 0.982 mmol) in anhydrous ethanol (3 mL, 51.4 mmol) was addedNaBH₄ (149 mg, 3.93 mmol) at 0° C. The reaction mixture was heated to80° C. for 30 min, then HCl 1N (1 mL) was added and ethanol wasevaporated. Dichloromethane was added to the reaction followed by brineand this was extracted with dichloromethane (3×). The organic layerswere dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified on silica gel column chromatography (100% CH₂Cl₂ upto 10% EtOAc/CH₂Cl₂) to provide the title material (25 mgs, 13%). LC(Method B): 1.858 min. LCMS (APCI) calcd for C₉H₉N₂OS [M+H]⁺ m/z 193.04,found 193.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.89-8.03 (m, 2H), 7.46-7.62(m, 3H), 4.99 (d, J=5.87 Hz, 2H), 2.81 (t, J=6.06 Hz, 1H)

Example 72-Methoxy-6-(6-methoxy-4-((5-phenyl-1,2,4-thiadiazol-3-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 8.25 mg, 0.026 mmol) and(5-phenyl-1,2,4-thiadiazol-3-yl)methanol (Example 7B, 5 mg, 0.025 mmol)were put in a flask and this was flushed with N₂. Dry THF (4 mL) wasadded and to this resulting suspension was added tri-n-butylphosphine(0.017 mL, 0.065 mmol) and a solution of1,1′-(azodicarbonyl)dipiperidine (16.57 mg, 0.065 mmol) in dry THF (2.5mL) was added dropwise via a syringe pump over 2 h. The resulting beingsuspension was stirred for an additional 2 hours at RT, at which time LCshowed that no starting material remained. The mixture was diluted withEtOAc, washed with 0.2N HCl, sat. aqueous NaHCO₃ and brine, dried overanhydrous magnesium sulfate, filtered and concentrated. The residue waspurified on silica gel chromatography (50% dichloromethane/hexanes to100% dichloromethane to 1% EtOAc/CH₂Cl₂ to 7% EtOAc/CH₂Cl₂) andlyophilized in MeCN/water to give the title material (6.2 mgs, 49%). LC(Method B): 2.615 min. HRMS(ESI) calcd for C₂₃H₁₈N₅O₄S₂ [M+H]⁺ m/z492.0795. found 492.0828. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.00 (dd,J=8.02, 1.37 Hz, 2H), 7.85 (s, 1H), 7.50-7.56 (m, 3H), 7.14 (s, 1H),6.71-6.75 (m, 1H), 6.51 (d, J=1.57 Hz, 1H), 5.51 (s, 2H), 4.21 (s, 3H),3.84 (s, 3H).

Example 82-Methoxy-6-(6-methoxy-4-((5-phenyl-1,3,4-thiadiazol-2-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

8A. Ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 2-(2-benzoylhydrazinyl)-2-oxoacetate (1 g, 4.23mmol) in dry THF (5 ml, 61.0 mmol) was added the Lawesson's Reagent(1.079 g, 2.67 mmol). The reaction was stirred at r.t. for 2 h withoutany reaction. The mixture was then heated to 50° C. and then heated toreflux. Additional Lawesson's Reagent (1.079 g, 2.67 mmol) was added andafter 16h at reflux, the reaction was halfway completed. The mixture wasevaporated to dryness and the residue was purified by silica gel columnchromatography (50% CH₂Cl₂/hexanes up to 100% CH₂Cl₂) to provide thetitle material (0.35 g, 35%). LC (Method B): 2.063 min, LCMS (APCI)calcd for C₁₁H₁₁N₂O₂S [M+H]⁺ m/z 235.05, found 235.0. ¹H NMR (CDCl₃, 400MHz) δ ppm: 1.49 (t, J=1.00 Hz, 3H), 4.55 (q, J=1.00 Hz, 2H), 7.45-7.65(m, 3H), 8.02-8.07 (m, 2H).

8B. (5-Phenyl-1,3,4-thiadiazol-2-yl)methanol

To a solution of ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (350mgs, 1.494 mmol) in anhydrous methanol (5 mL, 124 mmol) was added NaBH₄(226 mgs, 5.98 mmol) at 0° C. The reaction mixture was stirred atambient temperature for 16 h. AcOH (2 mL) was added and the reaction wasconcentrated to dryness. The residue was dissolved in EtOAc, brine andwater and extracted with EtOAc (3×). The combined organic extracts werewashed with sat. aqueous NaHCO₃ and brine, and dried over anhydrousmagnesium sulfate. After filtration and evaporation, the residue wastriturated with ethyl ether to give the title material as a first crop(150 mgs, 52%). LC (Method B): 2.022 min, LCMS (APCI) calcd for C₉H₉N₂OS[M+H]⁺ m/z 193.04, found 193.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.92-8.03(m, 2H), 7.44-7.59 (m, 3H), 5.14 (br. d, J=3.90 Hz, 2H), 2.63 (br. s.,1H).

Example 82-Methoxy-6-(6-methoxy-4-((5-phenyl-1,3,4-thiadiazol-2-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 200 mL round-bottomed flask, benzene was added to ethyl5-phenyl-1,3,4-thiadiazole-2-carboxylate (Example 8B, 80 mgs, 0.252mmol) and6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 58.2 mgs, 0.303 mmol) and the mixture was sonificated for30 sec. and concentrated in vacuo to remove traces of water in thestarting material. Triphenylphosphine (99 mgs, 0.378 mmol) was added andthe mixture was dried on high vacuum for 10 min. THF (40 mL) were addedand the mixture was sonificated/heated for 5 min. Diisopropylazodicarboxylate (68.6 μl, 0.353 mmol) in THF (4 mL) was added dropwiseon app. 1 h and LC/MS showed that the reaction was not complete.Diisopropyl azodicarboxylate (2 drops) were added again and the mixturewas diluted in CH₂Cl₂, washed with sat. aqueous NaHCO₃ (1×), brine (1×),and dried over anhydrous MgSO₄ and concentrated. The residue waspurified on silica gel chromatography (100% CH₂Cl₂ up to 15%EtOAc/CH₂Cl₂) to give a residue which was triturated with MeCN andafforded the title material (36 mgs, 29%). LC (Method A): 2.901 min.HRMS(ESI) calcd for C₂₃H₁₇N₅O₄S₂ [M+H]⁺ m/z 492.0722, found 492.0806. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 7.96-8.02 (m, 2H), 7.87 (s, 1H), 7.45-7.55(m, 3H), 7.10 (s, 1H), 6.73-6.78 (m, 1H), 6.48 (d, J=1.57 Hz, 1H), 5.63(s, 2H), 4.22 (s, 3H), 3.86 (s, 3H).

Example 92-Methoxy-6-(6-methoxy-4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

9A.2-Methoxy-6-(6-methoxy-4-(prop-2-yn-1-yloxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A solution of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 205 mgs, 0.646 mmol) in THF (10 mL) was treated at r.t. andunder a nitrogen atmosphere, with propargyl alcohol (0.096 mL, 1.615mmol), tri-n-butylphosphine (0.398 mL, 1.615 mmol) and dropwise, over a25 min period with a solution of 1,1′-(azodicarbonyl)dipiperidine (408mgs, 1.615 mmol) in THF (10 mL). The mixture was sonicated in a bath for30 min and stirred at r.t. for another 30 min. The mixture was thendissolved in dichloromethane (50 mL) and washed with sat. aqueousNaHCO₃, brine and dried (MgSO₄). Evaporation of the solvent gave a solidthat was purified by silica gel column chromatography ISCO to give thetitle material (180 mg, 0.507 mmol, 78% yield). ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 8.38 (s, 1H), 6.92 (s, 1H), 6.86 (dd, J=1.8, 1.0 Hz, 1H),6.53 (d, J=1.6 Hz, 1H), 4.94 (d, J=2.7 Hz, 2H), 4.21 (s, 3H), 3.77-3.84(m, 3H), 3.60-3.66 (m, 1H).

9B. Azidobenzene

A solution of aniline (500 mgs, 5.37 mmol) in acetonitrile (10 mL, 191mmol) was cooled down in an ice bath and treated with tert-butyl nitrite(680 mgs, 6.59 mmol) and dropwise with TMS-N₃ (0.713 mL, 5.37 mmol). Theice bath was removed and the mixture was stirred overnight at r.t. underN₂. Acetonitrile was carefully evaporated (NB: azidobenzene is alsovolatile) and the residue (750 mgs) was passed through a silica gel pad(20 g) and eluted with petroleum ether (35-55° C.). Evaporation of thesolvent gave the title material as an oil (500 mgs, 4.20 mmol, 78%yield) that still contains some traces of solvent as shown by ¹H NMR. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 7.32-7.41 (m, 2H), 7.12-7.19 (m, 1H),7.01-7.09 (m, 2H).

Example 92-Methoxy-6-(6-methoxy-4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A solution of2-methoxy-6-(6-methoxy-4-(prop-2-yn-1-yloxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(Example 9A, 20 mgs, 0.056 mmol) and azidobenzene (Example 9B, 19 mgs,0.159 mmol) in DMF (4 mL, 51.7 mmol) was treated at r.t. and under anitrogen atmosphere with sodium(R)-2-(S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate(8 mgs, 0.040 mmol) and copper(II) sulfate pentahydrate (5 mgs, 0.020mmol). The mixture was stirred for 2 hours (reaction followed by HPLC)and was then diluted with dichloromethane (60 mL) and washed with sat.NaHCO₃, brine and dried (MgSO₄). The solvent was evaporated and thesolid residue was triturated with acetonitrile (2×1 mL) and lyophilizedto give the title material (13 mgs, 0.027 mmol, 49% yield). LC (MethodA): 2.213 min. HRMS(ESI) calcd for C₂₃H₁₉N₆O₄S [M+H]⁺ m/z 475.1183,found 475.1204. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 9.04 (s, 1H), 8.37 (s,1H), 7.90-7.99 (m, 2H), 7.58-7.67 (m, 2H), 7.51 (tt, J=7.4, 1.2 Hz, 1H),6.97-7.03 (m, 1H), 6.83-6.88 (m, 1H), 6.71 (d, J=1.6 Hz, 1H), 5.38 (s,3H), 4.20 (s, 3H), 3.83 (s, 3H).

Example 102-Methoxy-6-(6-methoxy-4-((1-phenyl-1H-1,2,3-triazol-5-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 5 mL microwave vial, was added2-methoxy-6-(6-methoxy-4-(prop-2-yn-1-yloxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(Example 9A, 27 mgs, 0.076 mmol), azidobenzene (Example 9B, 30 mgs,0.252 mmol), anhydrous DMF (2.5 mL, 32.3 mmol) and (Cp*RuCl)₄ (12 mgs)under a nitrogen atmosphere. The vial was capped and heated at 110° C.for 20 min. in the microwave apparatus. The solvent was evaporated andthe residue was purified by silica gel chromatography ISCO, concentratedand twice triturated with methanol (2×1 mL). To the solid was addedacetonitrile (2 mL) and water (4 mL) and the mixture was freeze driedover the weekend to give the title material (5 mgs, 10.54 μmol, 14%yield). LC (Method F): 2.480 min. HRMS(ESI) calcd for C₂₃H₁₉N₆O₄S [M+H]⁺m/z 475.1183, found 475.1234. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.35 (s,1H), 8.12 (s, 1H), 7.66-7.73 (m, 2H), 7.53-7.63 (m, 3H), 6.84 (dd,J=2.0, 0.8 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 5.40 (s, 2H), 4.20 (s, 3H),3.79 (s, 3H).

Preparation of Alcohols

The following alcohols were prepared according to the proceduresdescribed in Examples 3 to 8.

HPLC Calc. LCMS Reten- [M + [M + tion Calc. H]⁺ − LCMS H]⁺ − Time [M +H]⁺ H₂O [M + H]⁺ H₂O (Min)/ Structure Formula m/z m/z m/z m/z Method NMR

C₁₁H₈F₃NOS 260.04  242.04 260.00 242.00 1.943/A ¹H NMR (CDCl₃) δ ppm:8.07 (d, J = 8.2 Hz, 2H) 7.71 (d, J = 8.2 Hz, 2H) 7.28 (s, 1H) 4.87 (d,J = 5.5 Hz, 2H) 2.31 (t, J = 5.5 Hz, 1H)

C₁₁H₁₁NOS 206.0634 189.06 206.1 188.1 1.842/A ¹H NMR (CDCl₃) δ ppm: 7.78(s, 1H) 7.70-7.75 (m, 1H) 7.30-7.36 (m, 1H) 7.23-7.27 (m, 1H) 7.16- 7.19(m, 1H) 4.84 (d, J = 5.5 Hz, 2H) 2.53 (t, J = 6.1 Hz, 1H) 2.42 (s, 3H)

C₁₁H₁₁NOS 206.0634 206.0674 1.616/C ¹H NMR (400 MHz, CDCl₃) δ ppm: 2.07(t, J = 5.1 Hz, 1H) 2.46 (s, 3H) 4.83 (d, J = 5.1 Hz, 2H) 7.34-7.51 (m,3H) 7.80-8.01 (m, 2H)

C₉H₁₃NO₂S 200.074  200.077 1.139/C ¹H NMR (400 MHz, CDCl₃) δ ppm:1.75-1.99 (m, 2H) 1.99-2.15 (m, 2H) 2.27-2.45 (m, 1H) 3.11-3.34 (m, 1H)3.55 (td, J = 11.74, 1.96 Hz, 2H) 4.08 (ddd, J = 11.74, 4.11, 1.37 Hz,2H) 4.76 (d, J = 5.87 Hz, 2H) 7.09 (d, J = 0.78 Hz, 1H)

C₁₀H₈FNOS 210.04  192.03 210 1.607/A ¹H NMR (400 MHz, CDCl₃) δ ppm:7.88-7.97 (m, 2H), 7.71 (t, J = 1.0 Hz, 1H), 7.10-7.18 (m, 2H), 4.91(dd, J = 6.1, 1.0 Hz, 2H), 1.92 (t, J = 6.1 Hz, 1H)

C₁₀H₈ClNOS 1.819/A ¹H NMR (400 MHz, CDCl₃) δ ppm: ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.15-8.2 (m, 1H), 7.45-7.5 (m, 1H), 7.3-7.41 (m, 3H), 4.85(d, J = 5.9 Hz, 2H), 2.33 (t, J = 5.9 Hz, 1H)

C₁₁H₈F₃NOS 260.0351 260.0362 1.987/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.19(s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.54 (broadt, 1H), 7.24 (s, 1H), 4.83 (s, 2H), 2.58 (broad s, 1H)

C₁₁H₁₁NO₂S 222.0583 222.0591 1.712/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.86(d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 4.79 (d, J= 6.1 Hz, 2H), 3.84 (s, 3H), 2.31 (t, J = 6.1 Hz, 1H).

C₁₁H₁₁NO₂S 222.0583 222.0598 1.659/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.36(dd, J = 8.8, 1.45 Hz, 1H), 7.35-7.40 (m, 1H), 7.21 (s, 1H), 7.06 (t, J= 7.8 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 5.9 Hz, 2H), 4.01(s, 3H), 2.34 (t, J = 5.9 Hz, 1H).

C₁₀H₁₅NOS 198.0947 198.0956 1.829/F ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.01(s, 1H), 4.72 (broad s, 2H), 2.91-3.0 (m, 1H), 2.56 (broad s, 1H),2.08-2.13 (m, 2H), 1.72-1.85 (m, 2H), 1.7-1.72 (m, 1H), 1.14-1.54 (m,5H).

C₉H₁₄N₂OS 1.188/F ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.34 (s, 1H), 4.51 (d,J = 5.8 Hz, 2H), 3.41-3.44 (m, 4H), 2.17 (t, J = 5.8 Hz, 1H), 1.59-1.68(m, 6H).

C₉H₁₅N₃OS 214.1009 214.1012 0.534/F ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.40(s, 1H), 4.52 (s, 2H), 3.48 (t, J = 5.2 Hz, 4H), 2.50 (t, J = 5.2 Hz,4H), 2.33 (s, 3H), 1.75 (broad s, 1H).

C₆H₉NOS 144.0478 144.0502 0.803/C ¹H NMR (400 MHz, CDCl₃) δ ppm: 1.39(t, J = 7.63 Hz, 3 H) 2.90-3.15 (m, 3 H) 4.74 (d, J = 5.87 Hz, 2 H) 7.04(s, 1 H)

C₁₀H₇F₂NOS 228.03  210.02 228 210 ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.29(td, J = 8.7, 6.5 Hz, 1H), 7.29-7.33 (m, 1H), 6.92- 7.05 (m, 2H), 4.86(d, J = 6.0 Hz, 2H), 2.32 (t, J = 6.1 Hz, 1H)

C₁₀H₈FNOS 210.04  192.03 210 192 1.738/A ¹H NMR (400 MHz, CDCl₃) δ ppm:7.65-7.74 (m, 2H), 7.41 (td, J = 7.9, 5.7 Hz, 1H), 7.23 (s, 1H), 7.13(td, J = 8.4, 2.7 Hz, 1H), 4.84 (d, J = 5.9 Hz, 2H), 2.42 (t, J = 5.9Hz, 1H)

C₁₀H₈FNOS 210.04  192.03 210 192 1.741/A ¹H NMR (400 MHz, CDCl₃) δ ppm:8.21 (td, J = 7.7, 1.8 Hz, 1H), 7.31-7.40 (m, 1H), 7.27 (s, 1H),7.11-7.24 (m, 2H), 4.82 (d, J = 6.0 Hz, 2H), 2.86 (t, J = 6.1 Hz, 1H)

C₁₀H₈ClNOS 226.01  208.00 226 208 1.902/A ¹H NMR (400 MHz, CDCl₃) δ ppm:7.87-7.91 (m, 2H), 7.39- 7.45 (m, 2H), 7.21 (t, J = 1.0 Hz, 1H), 4.84(d, J = 5.7 Hz, 2H), 2.31 (t, J = 5.7 Hz, 1H)

C₉H₈N₂OS 193.04  175.03 193 175 1.248/B ¹H NMR (400 MHz, CDCl₃) δ ppm:8.71 (d, J = 6.2 Hz, 2H), 7.81 (d, J = 6.2 Hz, 2H), 7.35 (s, 1H), 4.88(d, J = 3.9 Hz, 2H), 2.45 (br. s., 1H)

C₁₁H₈F₃NO₂S 276.03  258.02 276 258 2.020/A ¹H NMR (400 MHz, CDCl₃) δppm: 7.98 (dd, J = 8.1, 4.8 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.22 (s,1H), 4.84 (d, J = 5.5 Hz, 2H), 2.47 (t, J = 5.5 Hz, 1H)

C₉H₈N₂OS 193.04  175.03 193 1.152/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 9.11(d, J = 2.0 Hz, 1H), 8.66 (dd, J = 4.9, 1.4 Hz, 1H), 8.28 (dt, J = 8.2,2.0 Hz, 1H), 7.58 (s, 1H), 7.53 (dd, J = 7.8, 4.7 Hz, 1H), 5.44 (t, J =5.8 Hz, 1H), 4.65 (d, J = 5.9 Hz, 2H)

C₉H₁₂F₂N₂OS 235.07  217.06 235 217 1.293/A ¹H NMR (400 MHz, CDCl₃) δppm: 6.46 (s, 1H), 4.55 (br. s., 2H), 3.66 (dd, J = 6.0 Hz, 4H), 2.17(br. s., 1H), 2.02-2.15 (m, 4H)

C₈H₇N₃OS 194.04  176.03 194 176 1.577/B ¹H NMR (400 MHz, CDCl₃) δ ppm:9.43 (br. d, J = 1.60 Hz, 1H), 8.62 (d, J = 2.74 Hz, 1H), 8.56-8.60 (m,1H),7.40 (s, 1H), 4.89 (d, J = 5.87 Hz, 2H), 2.24 (t, J = 6.06 Hz, 1H)

C₄H₄BrNOS 193.93 175.92 176 1.101/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.18(d, J = 0.78 Hz, 1H), 4.76 (d, J = 1.00 Hz, 2H), 2.28-2.71 (m, 1H)

C₈H₈N₂O₂S 197.04  179.03 197 179 1.689/B ¹H NMR (400 MHz, CDCl₃) δ ppm:7.32 (s, 1H), 6.57 (br. d, J = 0.80 Hz, 1H), 4.86 (s, 2H), 2.52 (d, J =0.78 Hz, 3H)

C₈H₁₃NOS 172.0791 172.0788 1.528/A ¹H NMR (CDCl₃) δ ppm: 7.05 (s, 1H),4.75 (s, 2H), 2.87 (d, J = 7.0 Hz, 2H), 2.39 (br. s., 1H), 2.01-2.19 (m,1H), 1.00 (d, J = 6.6 Hz, 6H)

C₁₇H₁₁NOS 158.0634 158.0634 1.169/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.04(s, 1H), 4.75 (br. s., 2H), 3.25-3.39 (m, 1H), 2.44 (br. s., 1H), 1 (d,J = 6.6 Hz, 6H)

C₁₁H₉NO₃S 236.0376 236.0386 1.900/A ¹H NMR (DMSO-d6) δ ppm: 7.41-7.46(m, 2H), 7.38 (t, J = 1.0 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.11 (s,2H), 5.34 (br. s., 1H), 4.59 (broad s, 2H).

C₇H₈F₃NOS 212.0351 212.035 1.484/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.15(s, 1H), 4.78 (s, 2H), 3.28-3.36 (m, 2H), 3.1 (broad s, 1H), 2.65-2.79(m, 2H).

C₉H₁₃NOS₂ 216.0511 216.0516 1.705/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.14(s, 1H), 4.78 (s, 2H), 3.27 (broad s, 1H), 3.12-3.18 (m, 1H), 2.80-2.90(m, 2H), 2.70-2.78 (m, 2H), 2.42- 2.52 (m, 2H), 1.90-2.04 (m, 2H).

C₉H₁₃NOS 184.0791 184.0787 1.544/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.04(s, 1H), 4.74 (d, J = 5.9 Hz, 2H), 3.09 (t, J = 7.9 Hz, 2H), 2.65 (t, J= 6.1 Hz, 1H), 1.63-1.74 (m, 2H), 0.71-0.84 (m, 1H), 0.40- 0.53 (m, 2H),0.05-0.12 (m, 2H)

C₁₀H₁₆N₂O₂S 229.1005 229.1015 2.013/B ¹H NMR (400 MHz, CDCl₃) δ ppm:6.44 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.69-3.81 (m, 4H), 2.73 (t, J =11.5 Hz, 2H), 2.14 (t, J = 5.5 Hz, 1H), 1.26 (d, J = 5.9 Hz, 6H)

C₈H₁₂N₂OS₂ 217.0464 217.0467 1.13/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.42(s, 1H), 4.54 (s, 2H), 3.78-3.90 (m, 4H), 2.67-2.76 (m, 4H), 2.05-2.18(m, 1H)

C₉H₁₄N₂O₂S 215.0849 215.0845 0.93/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.35(s, 1H), 4.54 (broad s, 2H), 3.83-3.89 (m, 2H), 3.76-3.81 (m, 4H),3.68-3.76 (m, 2H), 2.47 (br. s., 1H), 2.02-2.10 (m, 2H).

Preparation of Bromides

The following bromides were prepared according to the proceduredescribed in Example 4.

HPLC Calc. LCMS Retention [M + H]⁺ [M + H]⁺ Time (Min)/ StructureFormula m/z m/z Method NMR

C₁₀H₈BrNS 253.9634 253.9654  2.10/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 4.65(s, 2 H), 7.31 (s, 1 H), 7.42-7.49 (m, 3 H), 7.93-8.00 (m, 2 H)

C₉H₁₂BrNOS 261.9896 261.9903 1.535/A ¹H NMR (400 MHz, CDCl₃) δ ppm:1.79- 1.99 (m, 2H) 1.99-2.13 (m, 2H) 3.27 (tt, J = 11.69, 3.96 Hz, 1H)3.54 (td, J = 11.74, 1.96 Hz, 2H) 4.00-4.17 (m, 2H) 4.57 (s, 2H) 7.21(s, 1H)

C₁₁H₁₀BrNS decomposed ¹H NMR (400 MHz, CDCl₃) δ ppm: 2.47 (s, 3H), 4.74(s, 2H) 7.40-7.47 (m, 3H) 7.87-7.94 (m, 2H)

C₁₀H₇BrFNS 271.9539 271.9543 2.165/A ¹H NMR (400 MHz, CDCl₃) δ ppm:7.88- 7.97 (m, 2H), 7.78 (s, 1H), 7.09-7.19 (m, 2H), 4.76 (s, 2H).

C₁₀H₇BrClNS ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.2- 8.5 (m, 1H), 7.45-7.5(m, 1H), 7.44 (s, 1H), 7.3-7.4 (m, 2H), 4.65 (s, 2H).

C₁₁H₇BrF₃NS ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.20 (s, 1H), 8.10 (d, J =7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.35(s, 1H), 4.62 (s, 2H).

C₁₁H₁₀BrNOS ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.87 (d, J = 8.9 Hz, 2H),7.21 (s, 1H), 6.93 (d, J = 8.9 Hz, 2H), 4.60 (s, 2H), 3.85 (s, 3H).

C₁₁H₁₀BrNOS ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.39 (dd, J = 7.8, 2.0 Hz,1H), 7.36-7.41 (m, 1H), 7.34 (s, 1H), 7.05-7.09 (m, 1H), 7.01 (d, J =8.16 Hz, 1H), 4.65 (s, 2H), 4.0 (s, 3H).

C₈H₁₁BrN₂OS 262.9848 262.9864 1.625/F ¹H NMR (400 MHz, CDCl₃) δ ppm:6.52 (s, 1H) 4.32 (s, 2H), 3.74 (t, J = 5.05 Hz, 4H), 3.40 (t, J = 5.05Hz, 4H).

C₁₀H₁₄BrNS 260.0103 260.0127 2.184/F ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.13(s, 1H), 4.54 (s, 2H), 2.94-3.03 (m, 1H), 2.10-2.14 (m, 2H), 1.80-1.86(m, 2H), 1.69-1.75 (m, 1H), 1.2-1.54 (m, 5H).

C₉H₁₃BrN₂S 261.0056 261.0067 1.604/F ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.49(s, 1H), 4.36 (s, 2H), 3.42-3.45 (m, 4H), 1.59-1.69 (m, 6H).

C₆H₈BrNS 205.96  207.96  206    208    1.748/F ¹H NMR (400 MHz, CDCl₃) δppm: 7.17 (s, 1H), 4.56 (s, 2H), 3.04 (q, J = 7.4 Hz, 2H), 1.28-1.49 (m,3H)

C₁₀H₆BrF₂NS 289.94  291.94  290    292    2.134/A ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.33 (td, J = 8.7, 6.5 Hz, 1H), 7.42 (s, 1H), 6.91-7.05(m, 2H), 4.66 (d, J = 0.8 Hz, 2H)

C₁₀H₇BrFNS 271.95  273.95  272    274    1.986/A ¹H NMR (400 MHz, CDCl₃)δ ppm: 7.67- 7.75 (m, 2H), 7.38-7.46 (m, 1H), 7.34 (s, 1H), 7.11-7.18(m, 1H), 4.64 (s, 2H)

C₁₀H₇BrFNS 271.95  273.95  272    274    2.082/A ¹H NMR (400 MHz, CDCl₃)δ ppm: 8.28- 8.36 (m, 1H), 7.38-7.47 (m, 2H), 7.24- 7.30 (m, 2H), 7.20(dd, J = 11.3, 8.2 Hz, 1H), 4.67 (s, 2H)

C₁₀H₇BrClNS 287.92  289.92  288    290    2.223/F ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.90 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.32(s, 1H), 4.63 (s, 2H)

C₁₁H₇BrF₃NOS 337.95  339.94  338    340    2.251/A ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.00 (dd, J = 9.0, 1.0 Hz, 2H), 7.33 (s, 1H), 7.30 (dd, J= 9.0, 1.0 Hz, 2H), 4.64 (s, 2H)

C₉H₇BrN₂S 254.96  256.96  255    257    1.828/B

C₄H₃Br₂NS 255.84  257.84  256    258    1.813/B

C₈H₁₂BrNS 233.9947 233.996  2.022/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.17(s, 1H), 4.57 (s, 2H), 2.88 (d, J = 7.4 Hz, 2H), 2.05-2.16 (m, 1H), 1.00(d, J = 6.7 Hz, 6H)

C₇H₁₀BrNS 219.979  219.9792  1.89/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.17(s, 1H), 4.57 (s, 2H), 3.28-3.38 (m, 1H), 1.41 (d, J = 6.7 Hz, 6H)

C₁₁H₈BrNO₂S 297.9532 297.9545 2.185/A ¹H NMR (400 MHz, CDCl₃) δ ppm:7.43- 7.53 (m, 2H), 7.26 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.05 (s,2H), 4.64 (s, 2H).

C₇H₇BrF₃NS 273.9507 273.9511 1.918/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.21(s, 1H), 4.55 (s, 2H), 3.21-3.30 (m, 2H), 2.59-2.77 (m, 2H)

C₁₀H₁₅BrN₂OS 291.0161 291.018  1.911/A ¹H NMR (400 MHz, CDCl₃) δ ppm:6.58 (s, 1H), 4.39 (s, 2H), 3.70-3.81 (m, 4H), 2.74 (dd, J = 12.9, 11.0Hz, 2H), 1.26 (d, J = 6.3 Hz, 6H)

C₈H₁₁BrN₂S₂ 278.962  278.9636 1.912/A ¹H NMR (400 MHz, CDCl₃) δ ppm:6.57 (s, 1H), 4.37 (s, 2H), 3.79-3.90 (m, 4H), 2.67-2.79 (m, 4H).

C₉H₁₃BrN₂OS 277.0005 277.0017 1.437/A ¹H NMR (400 MHz, CDCl₃) δ ppm:6.53 (s, 1H), 4.47 (s, 2H), 3.87-3.94 (m, 2H), 3.84-3.87 (m, 2H),3.75-3.83 (m, 4H), 2.03-2.10 (m, 2H).

Examples 11 to 35

The following additional Examples have been prepared, isolated andcharacterized using the methods disclosed above.

HPLC Re- tention Calc. Time LCMS [M + H]⁺ (Min)/ [M + H]⁺ Ex. StructureFormula m/z Method m/z NMR 11

C₂₅H₁₇F₃N₄O₄S₂ 559.0716 2.501/A 559.0725 ¹H NMR (CDCl₃) δ ppm: 8.10 (d,J = 8.2 Hz, 2H), 7.86 (s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.44-7.48 (m,1H), 7.12 (s, 1H), 6.71-6.75 (m, 1H), 6.48 (d, J = 1.6 Hz, 1H), 5.41 (d,J = 0.8 Hz, 2H), 4.22 (s, 3H), 3.86 (s, 3H) 12

C₂₅H₂₀N₄O₄S₂ 505.0999 2.506/A 505.1012 ¹H NMR (CDCl₃) δ ppm: 8.10 (d, J= 8.2 Hz, 2H) 7.86 (s, 1H) 7.72 (d, J = 8.2 Hz, 2H) 7.44-7.48 (m, 1H)7.12 (s, 1H) 6.71-6.75 (m, 1H) 6.48 (d, J = 1.6 Hz, 1H) 5.41 (d, J = 0.8Hz, 2H) 4.22 (s, 3H) 3.86 (s, 3H) 13

C₂₅H₂₀N₄O₄S₂ 505.0999 2.498/C 505.1197 ¹H NMR (400 MHz, CDCl₃) δ ppm2.53 (s, 3H) 3.87 (s, 3H) 4.21 (s, 3H) 5.31 (s, 2H) 6.44 (d, J = 1.56Hz, 1H) 6.74 (broad d, 1H) 7.06 (s, 1H) 7.38-7.48 (m, 3H) 7.85 (s, 1H)7.90-7.97 (m, 2H) 14

C₂₃H₂₂N₄O₅S₂ 499.1104 2.303/C 499.1139 ¹H NMR (400 MHz, CDCl₃) δ ppm:1.82-2.02 (m, 2H) 2.02- 2.20 (m, 2H) 3.21-3.35 (m, 1H) 3.56 (td, J =11.74, 1.96 Hz, 2H) 3.85 (s, 3H) 4.05-4.13 (m, 2H) 4.22 (s, 3H) 5.31 (s,2H) 6.44 (d, J = 1.96 Hz, 1H) 6.71 (d, J = 0.78 Hz, 1H) 7.09 (s, 1H)7.85 (s, 1H) 15

C₂₄H₁₇FN₄O₄S₂ 509.0748 2.637/B 509.0769 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.9-7.97 (m, 2H), 7.82 (s, 1H), 7.33 (s, 1H), 7.13-7.15 (m, 2H), 7.12(s, 1H), 6.70 (d, J = 1.87 Hz, 1H), 6.44 (d, J = 1.87 Hz, 1H), 5.36 (s,2H), 4.19 (s, 3H), 3.83 (s, 3H). 16

C₂₄H₁₇ClN₄O₄S₂ 525.0453 2.502/A 525.0458 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.2-8.25 (m, 1H), 7.83 (s, 1H), 7.52 (s, 1H), 7.48-7.50 (m, 1H),7.31-7.39 (m, 2H), 7.10 (s, 1H), 6.70 (broad d, 1H), 6.46 (d, J = 1.88Hz, 1H), 5.41 (s, 2H), 4.19 (s, 3H), 3.83 (s, 3H). 17

C₂₅H₁₇F₃N₄O₄S₂ 559.0716 2.534/A 559.0752 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.23 (broad s, 1H), 8.12 (broad d, J = 7.9 Hz, 1H), 7.83 (s, 1H), 7.67(broad d, J = 7.9 Hz, 1H), 7.57 (broad t, J = 7.9 Hz, 1H), 7.42 (s, 1H),7.10 (s, 1H), 6.70 (broad d, 1H), 6.46 (d, J = 1.54 Hz, 1H), 5.39 (s,2H), 4.19 (s, 3H), 3.83 (s, 3H). 18

C₂₅H₂₀N₄O₅S₂ 521.0948 2.451/A 521.0977 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.86-7.90 (m, 2H), 7.83 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 6.93-6.96(m, 2H), 6.69 (broad d, 1H), 6.45 (d, J = 1.7 Hz, 1H), 5.36 (s, 2H),4.19 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H). 19

C₂₅H₂₀N₄O₅S₂ 521.0948 2.460/A 521.0984 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.33 (dd, J = 7.84, 1.7 Hz, 1H), 7.77 (s, 1H), 7.35 (s, 1H), 7.29-7.34(m, 1H), 7.05 (s, 1H), 6.95-7.04 (m, 2H), 6.62 (d, J = 2.0 Hz, 1H), 6.40(d, J = 2.0 Hz, 1H), 5.34 (s, 2H), 4.12 (s, 3H), 3.96 (s, 3H), 3.76 (s,3H). 20

C₂₄H₂₄N₄O₄S₂ 497.1312 2.631/F 497.1350 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.82 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6.68 (broad d, 1H), 6.40 (d, J= 2.0 Hz, 1H), 5.27 (s, 2H), 4.19 (s, 3H), 3.82 (s, 3H), 2.95-3.03 (m,1H), 2.13- 2.16 (m, 2H), 1.82-1.87 (m, 2H), 1.7-1.75 (m, 1H), 1.12-1.58(m, 5H). 21

C₂₃H₂₃N₅O₄S₂ 498.1264 2.409/F 498.1329 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.82 (s, 1H), 7.08 (s, 1H), 6.68 (broad s, 1H), 6.53 (s, 1H), 6.41(broad s, 1H), 5.09 (s, 2H), 4.18 (s, 3H), 3.82 (s, 3H), 3.43-3.46 (m,4H), 1.60-1.68 (m, 6H). 22

C₂₃H₂₄N₆O₄S₂ 513.1373 2.208/F 513.1391 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.85 (s, 1H), 7.10 (s, 1H), 6.70 (d, J = 0.8 Hz, 1H), 6.61 (s, 1H), 6.43(d, J = 1.6 Hz, 1H), 5.12 (s, 2H), 4.21 (s, 3H), 3.84 (s, 3H), 3.53 (t,J = 1.0 Hz, 4H), 2.54 (t, J = 1.0 Hz, 4H), 2.36 (s, 3H). 23

C₂₀H₁₈N₄O₄S₂ 443.0842 2.491/F 443.0796 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.85 (s, 1H), 7.23 (s, 1H), 7.09 (s, 1H), 6.71 (d, J = 0.8 Hz, 1H), 6.43(d, J = 1.6 Hz, 1H), 5.30 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.07 (q,J = 7.4 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H) 24

C₂₄H₁₆F₂N₄O₄S₂ 527.0654 2.490/A 527.0661 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.33 (td, J = 8.6, 6.7 Hz, 1H), 7.86 (s, 1H), 7.49 (s, 1H), 7.12 (s,1H), 6.93-7.06 (m, 2H), 6.72 (d, J = 1.6 Hz, 1H), 6.47 (d, J = 1.6 Hz,1H), 5.41 (s, 2H), 4.22 (s, 3H), 3.85 (s, 3H) 25

C₂₄H₁₇FN₄O₄S₂ 509.0748 2.475/A 509.0757 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.86 (s, 1H), 7.68-7.77 (m, 2H), 7.39- 7.47 (m, 2H), 7.10-7.18 (m, 2H),6.70-6.75 (m, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.40 (s, 2H), 4.21 (s, 3H),3.85 (s, 3H) 26

C₂₄H₁₇FN₄O₄S₂ 509.0748 2.477/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.28-8.36(m, 1H), 7.86 (s, 1H), 7.51 (s, 1H), 7.38-7.46 (m, 1H), 7.28-7.31 (m,1H), 7.18- 7.25 (m, 1H), 7.13 (s, 1H), 6.73 (dd, J = 2.0, 0.8 Hz, 1H),6.48 (d, J = 2.0 Hz, 1H), 5.43 (s, 2H), 4.22 (s, 3H), 3.85 (s, 3H) 27

C₂₄H₁₇ClN₄O₄S₂ 2.668/F ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.28-8.36 (m, 1H),7.86 (s, 1H), 7.51 (s, 1H), 7.38-7.46 (m, 1H), 7.28-7.31 (m, 1H),7.18-7.25 (m, 1H), 7.13 (s, 1H), 6.73 (dd, J = 2.0, 0.8 Hz, 1H), 6.48(d, J = 2.0 Hz, 1H), 5.43 (s, 2H), 4.22 (s, 3H), 3.85 (s, 3H) 28

C₂₃H₁₇N₅O₄S₂ 492.0795 2.219/A 492.0822 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.68-8.73 (m, 2H), 7.83 (s, 1H), 7.79-7.83 (m, 2H), 7.49 (s, 1H),7.07-7.11 (m, 1H), 6.71 (d, J = 0.8 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H),5.38-5.41 (m, 2H), 4.19 (s, 3H), 3.83 (s, 3H) 29

C₂₅H₁₇F₃N₄O₅S₂ 575.0665 2.549/A 575.0691 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.01 (d, J = 8.6 Hz, 2H), 7.86 (s, 1H), 7.40 (d, J = 0.8 Hz, 1H), 7.31(d, J = 8.6 Hz, 2H), 7.12 (s, 1H), 6.70-6.75 (m, 1H), 6.45- 6.50 (m,1H), 5.39 (s, 2H), 4.22 (s, 3H), 3.85 (s, 3H) 30

C₂₃H₁₇N₅O₄S₂ 492.0795 2.344/A 492.0815 ¹H NMR (400 MHz, CDCl₃) δ ppm:9.20 (d, J = 2.3 Hz, 1H), 8.68 (dd, J = 5.1, 1.6 Hz, 1H), 8.24- 8.31 (m,1H), 7.86 (s, 1H), 7.46 (s, 1H), 7.41 (dd, J = 7.8, 4.7 Hz, 1H), 7.12(s, 1H), 6.71-6.76 (m, 1H), 6.48 (d, J = 2.0 Hz, 1H), 5.42 (s, 2H), 4.22(s, 3H), 3.86 (s, 3H) 31

C₂₃H₂₁F₂N₅O₄S₂ 534.1076 2.428/A 534.1097 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.85 (s, 1H), 7.10 (s, 1H), 6.70 (d, J = 1.6 Hz, 1H), 6.64 (s, 1H), 6.44(d, J = 1.6 Hz, 1H), 5.11 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.63-3.73(m, 4H), 2.03-2.20 (m, 4H) 32

C₂₂H₁₆N₆O₄O₄S₂ 493.0747 2.371/A 493.0750 ¹H NMR (400 MHz, CDCl₃) δ ppm:3.86 (s, 1H), 4.22 (s, 1H), 5.43 (s, 1H), 6.45- 6.52 (m, 1H),6.73 (s,1H), 7.06-7.19 (m, 1H), 7.08- 7.15 (m, 1H), 7.57 (s, 1H), 7.82-7.90 (m,1H), 8.53-8.67 (m, 2H), 9.46 (s, 1H) 33

C₂₂H₁₇N₅O₅S₂ 496.0744 2.330/A 496.0757 ¹H NMR (400 MHz, CDCl₃) δ ppm:2.53 (d, J = 1.17 Hz, 3H), 3.85 (s, 3 H), 4.22 (s, 3H), 5.40 (d, J =0.78 Hz, 2H), 6.45 (d, J = 1.96 Hz, 1H), 6.56-6.63 (m, 1H), 6.73 (dd, J= 1.96, 0.78 Hz, 1H), 7.07-7.14 (m, 1H), 7.49 (t, J = 0.98 Hz, 1H), 7.86(s, 1H) 34

C₁₈H₁₄N₄O₄S₂ 415.0529 2.193/A 415.0546 ¹H NMR (400 MHz, CDCl₃) δ ppm:3.85 (s, 3H), 4.22 (s, 3H), 5.38-5.43 (m, 2H), 6.45 (d, J = 1.96 Hz,1H), 6.70-6.74 (m, 1H), 7.10 (s, 1H), 7.40-7.49 (m, 1H), 7.85 (s, 1H),8.85 (d, J = 1.96 Hz, 1H) 35

C₁₈H₁₃BrN₄O₄S₂ 494.9614 2.333/A 494.9620 ¹H NMR (400 MHz, CDCl₃) δ ppm:3.85 (s, 3H), 4.19-4.25 (m, 3H), 5.30 (s, 2H), 6.40 (s, 1H), 6.72 (s,1H), 7.08 (s, 1H), 7.30-7.38 (m, 1H), 7.86 (s, 1H)

Example 364-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methypthiazol-2-yl)-N,N-dimethylbenzamide

36A.4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

In a 350 mL glass pressure flask, a mixture of2-bromo-4-(((tert-butyldimethylsilyl)oxy)-methyl)thiazole (Example 37B,3.00 g, 9.73 mmol), (4-(dimethylcarbamoyl)phenyl)-boronic acid (2.82 g,14.61 mmol) in toluene (90 mL) and EtOH (30 mL) was treated with 2 MNa₂CO₃ (6.0 mL, 12.0 mmol) and the resulting heterogeneous mixture wasflushed with nitrogen for 10 min. To this mixture was addedPd(dppf)Cl2.DCM (0.50 g, 0.61 mmol) and the sealed vial was heated at95° C. for 2 h. The cooled reaction mixture was then partitioned betweenethyl acetate and saturated sodium bicarbonate. The organic phase wasseparated, washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The light yellow syrup obtained waschromatographed on silica gel (elution with 0-20% ethylacetate-dichloromethane) to give 3.24 g (88%) of the title material as aclear syrup. LC (Method A): 2.401 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.97 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.48-7.54 (s, 1H), 4.83(s, 2H), 3.00 (br. s., 3H), 2.93 (br. s., 3H), 0.91 (s, 9H), 0.11 (s,6H).

36B. 4-(4-(Hydroxymethyl)thiazol-2-yl)-N,N-dimethylbenzamide

A solution of4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide(3.24 g, 8.6 mmol) in tetrahydrofuran (150 mL) was treated withtriethylamine trihydrofluoride (7.0 mL, 43.0 mmol) and the resultingclear solution was stirred at 23° C. for 18 h. The reaction mixture wasthen quenched with saturated aqueous sodium bicarbonate (100 mL) andstirred for 10 min. The reaction mixture was extracted withdichloromethane (3×250 mL) and the combined organic phase was washedwith saturated sodium bicarbonate and brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue obtained waschromatographed on silica gel (elution with 50-100% ethylacetate-dichloromethane) to give 1.98 g (88%) of the title material as awhite solid. LC (Method A): 1.762 min. HRMS(ESI) Anal.Calcd forC₁₃H₁₅N₂O₂S [M+H]⁺ m/z 263.0849; found 263.0865. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 7.96 (d, J=7.8 Hz, 2H), 7.49 (d, J=7.8 Hz, 2H), 7.22 (s, 1H),4.82 (s, 2H), 3.13 (br. s., 3H), 3.00 (br. s., 3H), 2.66 (br. s., 1H).

Example 364-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 1.00 g, 3.15 mmol) and4-(4-(hydroxymethyl)thiazol-2-yl)-N,N-dimethylbenzamide (Example 36B,0.950 g, 3.62 mmol) in dry tetrahydrofuran (80 mL) was treated at 22° C.and under nitrogen with tri-n-butylphosphine (2.0 mL, 8.11 mmol) addedin one portion, followed by a solution of1,1′-(azodicarbonyl)dipiperidine (2.00 g, 7.93 mmol) in tetrahydrofuran(20 mL) added dropwise over 40 min. After another 2 h at 22° C., thereaction mixture was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate. The organic phase was washed with brine,dried over anhydrous magnesium sulfate and concentrated in vacuo to givea glassy residue. Chromatography on silica gel (elution gradient ofethyl acetate in dichloromethane) gave 1.343 g (66%) of the titlematerial as a white solid after trituration in acetonitrile. LC (MethodA): 2.597 min. HRMS(ESI) Anal.Calcd for C₂₇H₂₄N₅O₅S₂ [M+H]⁺ m/z562.1213; found 562.1216. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.02 (d, J=8.0Hz, 2H), 7.86 (s, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.42 (s, 1H), 7.12 (s,1H), 6.73 (br s, 1H), 6.48 (br s, 1H), 5.41 (s, 2H), 4.22 (s, 3H), 3.86(s, 3H), 3.15 (br s, 3H), 3.02 (br s, 3H).

Example 37 Methyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoate

37A. (2-Bromothiazol-4-yl)methanol

A solution of methyl 2-bromothiazole-4-carboxylate (0.500 g, 2.25 mmol)in EtOH (10 mL) in a 50 mL flask under a nitrogen atmosphere was cooledto 0° C. and treated with NaBH₄ (170 mg, 4.50 mmol) portion-wise over 5min. After stirring for 15 min at 0° C., the reaction mixture was heatedat 90° C. for 1 h. The cooled mixture was then quenched with saturatedaqueous NH₄Cl (15 mL) and stirring was continued for 20 min. Ethylacetate (50 mL) was then added and the organic phase was separated,washed with brine, dried over MgSO₄ and concentrated to give the titlecompound (0.212 g, 49%) which was used as such in the next step. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.18 (s, 1H), 4.76 (s, 2H), 2.21 (br s, 1H).

37B. 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole

To an ice-cold solution of (2-bromothiazol-4-yl)methanol (0.212 g, 1.09mmol) in DMF (10 mL) was added TBDMSC1 (0.329 g, 2.19 mmol), followed byimidazole (0.171 g, 2.51 mmol). The reaction mixture was then allowed towarm to room temperature over 10 min and stirred for 18 h under N₂. Thereaction was quenched by the addition of EtOH at 0° C. and the mixturewas stirred at 20° C. for 10 min before being partitioned with EtOAc andsaturated aqueous NaHCO₃. The organic layer was separated, washed withbrine, dried over MgSO₄ and filtered. The residue was purified on theISCO using a REDISEP® 12 g column (0 to 5% EtOAc-DCM) to afford thedesired product as yellow oil (0.333 g, 99%). LCMS (APCI): calcd forC₁₀H₁₉BrNOSSi [M+H]⁺ m/z 308.01, found 308.0. ¹H NMR (CDCl₃, 400 MHz) δppm: 7.14 (t, J=1.5 Hz, 1H), 4.83 (d, J=1.6 Hz, 2H), 0.95 (s, 9H), 0.12(s, 6H).

37C. Methyl4-(4-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)benzoate

A mixture of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(0.150 g, 0.487 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (0.119g, 0.662 mmol) in tetrahydrofuran (4 mL) was treated with potassiumfluoride (0.085 g, 1.460 mmol), 2-(di-t-butylphosphino)biphenyl (0.015g, 0.049 mmol) and palladium(II) acetate (5.5 mg, 0.024 mmol). Thereaction mixture was purged with nitrogen for 5 min and then heated at70° C. for 16 h. The cooled reaction mixture was concentrated and theresidue chromatographed on silica gel (ISCO, elution gradient ofdichloromethane in hexane) to give 0.050 g (28%) of the title material.LC (Method B): 2.793 min. LCMS (APCI): calcd for C₁₈H₂₆NO₃SSi [M+H]⁺ m/z364.14; found 364.2. ¹H NMR (400 MHz, acetone-d₆) δ ppm: 8.11 (s, 4H),7.51 (s, 1H), 4.92 (d, J=1.17 Hz, 2H), 3.92 (s, 3H), 0.97 (s, 9H), 0.16(s, 6H).

37D. Methyl 4-(4-(hydroxymethyl)thiazol-2-yl)benzoate

A solution of methyl4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)benzoate (0.050g, 0.138 mmol) in dry tetrahydrofuran (10 mL) under nitrogen was treateddropwise with triethylamine trihydrofluoride (0.112 mL, 0.688 mmol) andthe solution was stirred at room temperature for 16 h. The reactionmixture was then partitioned with dichloromethane-saturated aqueoussodium bicarbonate and the organic phase was separated, washed withbrine, dried over anhydrous magnesium sulfate and concentrated in vacuo.This gave 0.030 g (88%) of the title material as a beige foam which wasused as such for the next step. LC (Method B): 2.049 min. LCMS (APCI):calcd for C₁₂H₁₂NO₃S [M+H]⁺ m/z 250.05; found 250.2. ¹H NMR (400 MHz,acetone-d₆) δ ppm: 8.09 (s, 4H), 7.51 (s, 1H), 4.73-4.87 (m, 2H), 3.91(s, 3H), 2.83 (br s, 1H).

Example 37 Methyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoate

The title compound was prepared according to the general couplingprocedure described in Example 36 to give a solid. LC (Method A): 2.488min. HRMS(ESI) calcd for C₂₆H₂₁N₄O₆S₂[M+H]⁺ m/z 549.0903; found549.0913. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.37 (s, 1H), 8.05-8.16 (m,4H), 8.01 (s, 1H), 7.03 (s, 1H), 6.85 (br s, 1H), 6.65 (d, J=1.96 Hz,1H), 5.40 (s, 2H), 4.20 (s, 3H), 3.89 (s, 3H), 3.82 (s, 3H).

Example 382-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)phenyl)propan-2-ol

38A.2-(4-(4-4-(((tert-Butyldimethylsilyl)oxy)methypthiazol-2-yl)phenyl)propan-2-ol

An ice-cold solution of methyl 4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)benzoate (Example 37C, 0.150g, 0.413 mmol) in tetrahydrofuran (5 mL) was treated withmethylmagnesium bromide (1 M in butyl ether, 1.65 mL, 1.65 mmol). Thecooling bath was then removed and the mixture was stirred at roomtemperature for 30 min before being partitioned between ethyl acetateand an aqueous solution of citric acid. The organic layer was separated,washed with brine, dried over anhydrous sodium sulfate and concentratedto give 0.100 g (67%) of the title material, which was used as such forthe next step. LC (Method B): 2.773 min. LCMS (APCI): calcd forC₁₉H₃₀NO₂SSi [M+H]⁺ m/z 364.18; found 364.2.

38B. 2-(4-(4-(Hydroxymethyl)thiazol-2-yl)phenyl)propan-2-ol

This compound was prepared according to the deprotection proceduredescribed in Example 37D. LC (Method A): 1.584 min. HRMS(ESI): calcd forC₁₃H₁₆NO₂S [M+H]⁺ m/z 250.0902; found 250.0895. ¹H NMR (400 MHz, CDCl₃)δ ppm: 7.92 (m, J=8.22 Hz, 2H), 7.57 (m, J=8.22 Hz, 2H), 7.18 (s, 1H),4.84 (d, J=5.87 Hz, 2H), 2.20-2.29 (m, 1H), 1.77 (s, 1H), 1.62 (s, 6H).

Example 382-(4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)phenyl)propan-2-ol

The title compound was prepared according to the Mitsunobu couplingprocedure described in Example 36. LC (Method A): 2.379 min. HRMS(ESI):calcd for C₂₇H₂₅N₄O₅S₂[M+H]⁺ m/z 549.1266; found 549.1221. ¹H NMR (400MHz, CDCl₃) δ ppm: 7.95 (m, J=8.4 Hz, 2H), 7.86 (s, 1H), 7.59 (m, J=8.4Hz, 2H), 7.36 (s, 1H), 7.12 (s, 1H), 6.72 (s, 1H), 6.45-6.52 (m, 1H),5.40 (s, 2H), 4.22 (s, 3H), 3.85 (s, 3H), 1.77 (s, 1H), 1.63 (s, 6H).

Example 394-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methypthiazol-2-yl)-N-(2-methoxyethyl)-N-methylbenzamide

39A. tert-Butyl4-(4-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)benzoate

A mixture of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 1.542 g, 5.000 mmol) and(4-(tert-butoxycarbonyl)phenyl)boronic acid (1.388 g, 6.25 mmol) intoluene-tert-butanol (3:1, 60 mL) was purged with a stream of N₂ bubblesfor 15 min in a sealable flask. To this mixture was addedPd(dppf)Cl₂.DCM (0.204 g, 0.250 mmol) and 2 M Na₂CO₃ (3.13 mL, 6.25mmol), the flask was sealed and the mixture was stirred at 95° C. (oilbath temperature) for 4 h. Another 0.25 equiv of the boronic acid and 2M Na₂CO₃ were added, together with a small amount of the catalyst. Themixture was heated at 95° C. for another 2 h before being allowed tocool to room temperature and then partitioned with EtOAc-water. Theorganic phase was separated, washed (brine), dried (Na₂SO₄) andevaporated to give a dark brown gum. Flash chromatography (Isco/0-10%EtOAc-hexane) of this gum afforded the title compound (1.065 g, 52.5%)as a colorless gum. This material was used as such in the next step. LC(Method B): 3.407 min. LCMS (APCI): calcd for C₂₁H₃₂NO₃SSi [M+H]⁺ m/z406.19; found 406.2. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.04 (d, J=8.6 Hz,2H), 7.98 (d, J=8.6 Hz, 2H), 7.26 (s, 1H), 4.79 (s, 2H), 1.47 (s, 9H),0.82 (s, 9H), 0.10 (s, 6H).

39B. tert-Butyl 4-(4-(hydroxymethyl)thiazol-2-yl)benzoate

To a solution of tert-butyl4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)benzoate (1.058g, 2.61 mmol) in dry THF (25 mL) under N₂ was added triethylaminetrihydrofluoride (1.274 mL, 7.82 mmol) dropwise and the mixture wasstirred at room temperature for 18 h. The resulting mixture waspartitioned with EtOAc-saturated aqueous NaHCO₃ and the organic phasewas separated, dried (Na₂SO₄) and evaporated to give the title compound(0.760 g, 100%) as a colorless gum which crystallized on standing invacuo. This material was essentially pure and was used as such in thenext step. LC (Method B): 2.239 min. LCMS (APCI): calcd for C₁₅H₁₈NO₃S[M+H]⁺ m/z 292.10; found 292.2. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.18-7.92(m, 4H), 7.27 (s, 1H), 4.86 (d, J=5.87 Hz, 2H), 2.41-2.22 (m, 1H), 1.63(s, 9H).

39C. tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoate

The title compound was prepared according to the general Mitsunobucoupling procedure described in Example 36. LC (Method A) 2.599 min.HRMS(ESI): calcd for C₂₉H₂₇N₄O₆S₂ [M+H]⁺ m/z 591.1372; found 591.1363.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.99-8.10 (m, 4H), 7.86 (s, 1H), 7.44 (s,1H), 7.12 (s, 1H), 6.71-6.75 (m, 1H), 6.46-6.49 (m, 1H), 5.42 (s, 2H),4.22 (s, 3H), 3.86 (s, 3H), 1.63 (s, 9H).

39D.4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoicacid

To a solution of tert-butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thia-diazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoate(0.841 g, 1.424 mmol) in DCM (6 mL) was added TFA (3 mL) and theresulting pale yellowish solution was stirred at room temperature for 4h before the volatiles were removed in vacuo. The residue was trituratedwith a minimum volume of DCM and the resulting solid was filtered andthen lyophilized from DMSO. This gave the essentially pure titlecompound (0.701 g, 92%) as a solid which was used as such in the nextstep. LC (Method A): 2.347 min. HRMS(ESI): calcd for C₂₅H₁₉N₄O₆S₂ [M+H]⁺m/z 535.0746; found 535.0742. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 13.18 (brs, 1H), 8.37 (s, 1H), 8.03-8.13 (m, 4H), 8.00 (s, 1H), 7.01-7.06 (m,1H), 6.85 (d, J=0.78 Hz, 1H), 6.65 (d, J=1.96 Hz, 1H), 5.40 (s, 2H),4.20 (s, 3H), 3.82 (s, 3H).

Example 394-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N-(2-methoxyethyl)-N-methylbenzamide

To a solution of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoicacid (0.050 g, 0.094 mmol) in DMF (3 mL) was added DIEA (0.082 mL, 0.468mmol), followed by 2-methoxy-N-methylethanamine (0.0092 g, 0.103 mmol)and finally HATU (0.039 g, 0.103 mmol). The resulting mixture wasstirred at room temperature for 2 h before being evaporated to dryness.The residue was partitioned with DCM-water and the organic phase wasseparated, washed (saturated aqueous NaHCO₃), dried (Na₂SO₄) andadsorbed directly on a silica gel pre-column. Flash chromatography(Isco, elution gradient 0-80% EtOAc-DCM), followed by lyophilizationobtained material from MeCN-water afforded the title compound (0.044 g,78%) as a solid. LC (Method A): 2.325 min. HRMS(ESI): calcd. forC₂₉H₂₈N₅O₆S₂ [M+H]⁺ m/z 606.1481; found 606.1469. ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.01 (m, J=7.83 Hz, 2H), 7.86 (s, 1H), 7.49-7.56 (m, 2H),7.41 (s, 1H), 7.12 (s, 1H), 6.73 (s, 1H), 6.45-6.49 (m, 1H), 5.41 (s,2H), 4.22 (s, 3H), 3.86 (s, 3H), 3.65-3.81 (m, 2H), 3.45-3.53 (m, 2H),3.37-3.45 (m, 2H), 3.24-3.37 (m, 1H), 3.12-3.21 (m, 2H), 3.06-3.11 (m,1H).

Example 404-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N-methylbenzamide

The title compound was prepared according to the general amide couplingmethod described in Example 39. LC (Method A): 2.239 min. HRMS(ESI):calcd for C₂₆H₂₂N₅O₅S₂[M+H]⁺ m/z 548.1062; found 548.1058. ¹H NMR (400MHz, CDCl₃) δ ppm: 8.04 (d, J=8.22 Hz, 2H), 7.81-7.89 (m, 3H), 7.44 (s,1H), 7.12 (s, 1H), 6.66-6.78 (m, 1H), 6.44-6.50 (m, 1H), 6.14-6.24 (m,1H), 5.41 (s, 2H), 4.22 (s, 3H), 3.85 (s, 3H), 3.06 (d, J=5.09 Hz, 3H).

Example 41N-(tert-Butyl)-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzamide

The title compound was prepared according to the general amide couplingmethod described in Example 39. LC (Method A): 2.458 min. HRMS(ESI):calcd for C₂₉H₂₈N₅O₅S₂[M+H]⁺ m/z 590.1532; found 590.1536. ¹H NMR (400MHz, CDCl₃) δ ppm: 8.03 (m, 2H), 7.86 (s, 1H), 7.81 (m, 2H), 7.43 (s,1H), 7.12 (s, 1H), 6.73 (s, 1H), 6.48 (br s, 1H), 5.98 (s, 1H), 5.41 (s,2H), 4.22 (s, 3H), 3.86 (s, 3H), 1.51 (s, 9H).

Example 424-(5-Isopropyl-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

42A. Methyl 2-bromo-5-isopropylthiazole-4-carboxylate

To a solution of methyl 2-amino-5-isopropylthiazole-4-carboxylate (1.000g, 4.99 mmol) in CH₃CN (10 mL) was added isopentyl nitrite (1.073 mL,7.99 mmol) followed by copper(I) bromide (1.433 g, 9.99 mmol) and theresulting mixture was heated at 80° C. for 3 h. The reaction mixture wasthen concentrated under reduced pressure and the residue was partitionedbetween EtOAc and water. The organic phase was separated, filteredthrough a CELITE® pad and concentrated. The residue was purified on theISCO using a REDISEP® 24 g column (0 to 40% EtOAc-hexanes) to give thedesired product as a light red oil (0.787 g, 60%). LCMS (APCI): calcdfor C₈H₁₁BrNO₂S [M+H]⁺ m/z 263.962, found 264.0. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 4.17 (dt, J=13.7, 6.8 Hz, 1H), 3.94 (s, 3H), 1.35 (s, 3H), 1.33(s, 3H).

42B. (2-Bromo-5-isopropylthiazol-4-yl)methanol

The compound was prepared according to the procedure described inExample 37A. The reaction mixture was quenched with MeOH (10 mL) andstirred at room temperature for 10 min before being concentrated underreduced pressure. The residue was dissolved in DCM, washed withsaturated aqueous NaHCO₃, water and brine, dried over MgSO₄ andevaporated. The crude product was purified on the ISCO using a REDISEP®12 g column (0 to 15% MeOH-DCM) to give the desired product as a whitesolid (0.509 g, 72%). LCMS (APCI): calcd for C₇H₁₁BrNOS [M+H]⁺ m/z234.97, found 218.0 (M+H−OH). ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.64 (d,J=6.3 Hz, 2H), 3.32 (dt, J=13.7, 6.8 Hz, 1H), 2.26 (t, J=6.2 Hz, 1H),1.30 (d, J=6.8 Hz, 6H).

42C.2-Bromo-4-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-isopropylthiazole

The compound was prepared according to the procedure described inExample 37B. The crude product was purified on the ISCO using a REDISEP®12 g column (0 to 50% EtOAc-hexanes) to give the pure product as acolorless oil (0.744 g, 99%). LCMS (APCI): calcd for C₁₃H₂₅BrNOSSi[M+H]⁺ m/z 350.05, found 350.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.73 (s,2H), 3.47 (dt, J=13.7, 7.0 Hz, 1H), 1.29 (d, J=7.0 Hz, 6H), 0.91 (s,9H), 0.10 (s, 6H).

42D.4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-isopropylthiazol-2-yl)-N,N-dimethylbenzamide

In a 75 mL sealable tube were added2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-isopropylthiazole(0.200 g, 0.571 mmol), (4-(dimethylcarbamoyl)phenyl)boronic acid (0.166g, 0.859 mmol) and Pd(dppf)Cl₂.DCM (0.030 g, 0.037 mmol) in a mixture oftoluene-ethanol (3:1, 6.5 mL). The resulting orange solution wasdegassed with a stream of nitrogen bubbles for 15 min and then a 2 Maqueous solution of Na₂CO₃ (0.342 mL, 0.685 mmol) was added, thereaction vessel was sealed and the mixture was heated at 95° C. (bathtemperature) for 4 h. The cooled dark brown reaction mixture was dilutedwith EtOAc and washed with saturated aqueous NaHCO₃ and brine, driedover MgSO₄ and evaporated. The residue was purified on the ISCO using aREDISEP® 12 g column (0 to 60% EtOAc-DCM) to give the title compound asa colorless oil (0.080 g, 34%). LCMS (APCI): calcd for C₂₂H₃₅N₂O₂SSi[M+H]⁺ m/z 419.21, found 419.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.91-7.96(m, 2H), 7.45-7.49 (m, 2H), 4.84 (s, 2H), 3.51 (dt, J=13.6, 6.7 Hz, 1H),3.13 (br. s., 3H), 3.01 (br. s., 3H), 1.36 (s, 3H), 1.35 (s, 3H), 0.93(s, 9H), 0.13 (s, 6H).

42E. 4-(4-(Hydroxymethyl)-5-isopropylthiazol-2-yl)-N,N-dimethylbenzamide

The reaction was done according to the procedure of Example 37D. Thereaction mixture was diluted with DCM, washed with saturated aqueousNaHCO₃, water, and brine, dried over MgSO₄ and evaporated. The crudematerial was purified on the ISCO using a REDISEP® 4 g column (0 to 15%MeOH-DCM) to give the desired product as a yellow solid (0.056 g, 96%).LCMS (APCI): calcd for C₁₆H₂₁N₂O₂S [M+H]⁺ m/z 305.125, found 305.1. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 7.4 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz,2H), 4.74 (d, J=5.9 Hz, 2H), 3.34 (dt, J=13.6, 6.7 Hz, 1H), 3.14 (br.s., 3H), 3.01 (br. s., 3H), 2.45 (t, J=5.9 Hz, 1H), 1.36 (d, J=7.0 Hz,6H).

Example 424-(5-Isopropyl-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

The title compound was prepared according to the procedure used for thesynthesis of Example 36. The crude product was suspended in CH₃CN,sonicated, filtered and dried (×2) to give the title compound as anoff-white solid (0.018 g, 16%). LC (Method C): 2.359 min. HRMS(ESI):calcd for C₃₀H₃₀N₅O₅S₂ [M+H]⁺ m/z 604.161, found 604.1690. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.95-8.00 (m, J=8.2 Hz, 2H), 7.84 (s, 1H),7.47-7.52 (m, J=8.2 Hz, 2H), 7.02 (s, 1H), 6.71 (s, 1H), 6.60 (d, J=1.6Hz, 1H), 5.32 (s, 2H), 4.21 (s, 3H), 3.86 (s, 3H), 3.50 (dt, J=13.8, 7.0Hz, 1H), 3.14 (br s, 3H), 3.02 (br s, 3H), 1.37 (d, J=7.0 Hz, 6H).

Example 436-(4-((2-(2-Fluoropyridin-4-yl)-5-isopropylthiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

43A.4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(2-fluoropyridin-4-yl)-5-isopropylthiazole

The compound was prepared according to the procedure described forExample 42D. The crude product was purified on the ISCO using a REDISEP®12 g column (0 to 5% EtOAc-DCM) to give the product as a white solid(0.078 g, 38%). LCMS (APCI): calcd for C₁₈H₂₈FN₂OSSi [M+H]⁺ m/z 367.16,found 367.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.26 (d, J=5.3 Hz, 1H), 7.64(dt, J=5.3, 1.6 Hz, 1H), 7.42 (s, 1H), 4.85 (s, 2H), 3.54 (dt, J=13.7,6.8 Hz, 1H), 1.38 (s, 3H), 1.36 (s, 3H), 0.93 (s, 9H), 0.13 (s, 6H).

43B. (2-(2-Fluoropyridin-4-yl)-5-isopropylthiazol-4-yl)methanol

The compound was prepared using the procedure described in Example 37D.The reaction mixture was diluted with DCM, washed with saturated aqueousNaHCO₃, water and brine, dried over MgSO₄ and evaporated. The crudeproduct was purified on the ISCO using a REDISEP® 4 g column (0 to 15%MeOH-DCM) to give the desired product as a colorless solid (0.048 g,89%). LCMS (APCI): calcd for C₁₂H₁₃FN₂OS [M+H]⁺ m/z 253.073, found253.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.28 (d, J=5.1 Hz, 1H), 7.65 (dt,J=5.5, 1.6 Hz, 1H), 7.41-7.45 (m, 1H), 4.77 (d, J=5.9 Hz, 2H), 3.38 (dt,J=13.7, 6.8 Hz, 1H), 2.36 (t, J=5.9 Hz, 1H), 1.38 (d, J=6.9 Hz, 6H).

Example 436-(4-((2-(2-Fluoropyridin-4-yl)-5-isopropylthiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the procedure used for thesynthesis of Example 36. The crude product was suspended in CH₃CN,sonicated and filtered. The resulting solid was purified on the ISCOusing a REDISEP® 4 g column (0 to 40% EtOAc-DCM) to give the titlecompound as a yellow solid (0.063 g, 60%). LC (Method C): 2.457 min.HRMS(ESI): calcd for C₂₆H₂₃FN₅O₄S₂ [M+H]⁺ m/z 552.110, found 552.1181.¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.29 (d, J=5.5 Hz, 1H), 7.84 (s, 1H),7.68 (dt, J=5.5, 1.6 Hz, 1H), 7.46 (s, 1H), 7.02 (s, 1H), 6.72 (d, J=0.8Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 5.34 (s, 2H), 4.21 (s, 3H), 3.87 (s,3H), 3.53 (dt, J=13.6, 7.0 Hz, 1H), 1.39 (d, J=7.0 Hz, 6H).

Example 444-(5-Ethyl-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

44A. (2-Bromo-5-ethylthiazol-4-yl)methanol

The compound was prepared using the procedure described in Example 37A.The reaction mixture was quenched with MeOH (10 mL) and stirred at roomtemperature for 10 min. Then the mixture was concentrated under reducedpressure and the residue was dissolved in DCM, washed with saturatedaqueous NaHCO₃, water and brine, dried over MgSO₄ and evaporated to givethe desired product as colorless oil (0.156 g, 88%). LCMS (APCI): calcdfor C₆H₉BrNOS [M+H]⁺ m/z 220.95, found 205.9 (M+H−OH). ¹H NMR (CDCl₃,400 MHz) δ ppm: 4.63 (br. s., 2H), 2.82 (q, J=7.4 Hz, 2H), 2.29 (br. s.,1H), 1.28 (t, J=7.4 Hz, 3H).

44B. 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-ethylthiazole

The compound was prepared according to the procedure described inExample 37B. The crude product was purified on the ISCO using a REDISEP®12 g column (0 to 50% EtOAc-hexanes) to give the title compound as acolorless oil (0.173 g, 73%). LCMS (APCI): calcd for C₁₂H₂₃BrNOSSi[M+H]⁺ m/z 336.04, found 337.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.73 (s,2H), 2.88 (q, J=7.7 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H), 0.91 (s, 9H), 0.10(s, 6H).

44C.4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-ethylthiazol-2-yl)-N,N-dimethylbenzamide

The compound was prepared according to the procedure described forExample 36A. The crude product was purified on the ISCO using a REDISEP®4 g column (0 to 60% EtOAc-DCM) to give the title compound as brownishoil (0.155 g, 75%). LCMS (APCI): calcd for C₂₁H₃₃N₂O₂SSi [M+H]⁺ m/z405.20, found 405.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.90-7.96 (m, J=7.8Hz, 2H), 7.44-7.50 (m, J=8.2 Hz, 2H), 4.84 (s, 2H), 3.13 (br s, 3H),3.01 (br s, 3H), 2.96 (q, J=7.4 Hz, 2H), 1.34 (t, J=7.5 Hz, 3H), 0.93(s, 9H), 0.13 (s, 6H).

44D. 4-(5-Ethyl-4-(hydroxymethyl)thiazol-2-yl)-N,N-dimethylbenzamide

The compound was prepared according to the procedure described inExample 36B. The reaction mixture was diluted with DCM, washed withsaturated aqueous NaHCO₃, water and brine, dried over MgSO₄ andevaporated. The crude product was purified on the ISCO using a REDISEP®4 g column (0 to 15% MeOH-DCM) to give the desired product as acolorless oil (0.094 g, 85%). LCMS (APCI): calcd for C₁₅H₁₉N₂O₂S [M+H]⁺m/z 291.109, found 291.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.91-7.96 (m,J=8.2 Hz, 2H), 7.46-7.51 (m, J=8.2 Hz, 2H), 4.73 (d, J=5.9 Hz, 2H), 3.14(br. s., 3H), 3.01 (br. s., 3H), 2.89 (q, J=7.7 Hz, 2H), 2.40 (t, J=5.9Hz, 1H), 1.34 (t, J=7.6 Hz, 3H).

Example 444-(5-Ethyl-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

The title compound was prepared according to the procedure described forthe synthesis of Example 36. The crude product was suspended in CH₃CN,sonicated and filtered before being purified on the ISCO using aREDISEP® 4 g column (0 to 70%

EtOAc-DCM) to give the title compound as an off-white solid (0.059 g,49%). LC (Method C): 2.409 min. HRMS(ESI): calcd for C₂₉H₂₈N₅O₅S₂ [M+H]⁺m/z 590.145, found 590.1505. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.94-8.00(m, J=8.2 Hz, 2H), 7.84 (s, 1H), 7.46-7.52 (m, J=7.8 Hz, 2H), 7.04 (s,1H), 6.71 (d, J=0.8 Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 5.32 (s, 2H), 4.21(s, 3H), 3.86 (s, 3H), 3.14 (br s, 3H), 2.95-3.06 (m, 5H), 1.35 (t,J=7.6 Hz, 3H).

Example 45 tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)benzoate

45A. (2-Bromo-5-methylthiazol-4-yl)methanol

The compound was prepared according to the procedure described inExample 37A. The reaction mixture was quenched with MeOH (10 mL) andstirred at room temperature for 10 min. Then the mixture wasconcentrated under reduced pressure and the residue was dissolved inDCM, washed with saturated aqueous NaHCO₃, water and brine, dried overMgSO₄ and evaporated to give the desired product as colorless oil (0.843g, 96%). LCMS (APCI): calcd for C₅H₇BrNOS [M+H]⁺ m/z 207.94, found208.0.

45B. 2-Bromo-4-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole

The compound was prepared according to the procedure described inExample 37B. The crude product was purified on the ISCO using a REDISEP®40 g column (50 to 100% DCM-hexanes) to give the title compound as acolorless oil (0.682 g, 52%). LCMS (APCI): calcd for C₁₁H₂₁BrNOSSi[M+H]⁺ m/z 322.03, found 322.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.64 (s,2H), 2.34 (s, 3H), 0.81 (s, 9H), 0.00 (s, 6H).

45C. tert-Butyl4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)benzoate

In a sealable vial, a suspension of(4-(tert-butoxycarbonyl)phenyl)boronic acid (0.611 g, 2.75 mmol) and2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole (0.682g, 2.116 mmol) in toluene (34 mL) and ethanol (9.3 mL) was treated with2 M aqueous sodium carbonate (1.27 mL, 2.54 mmol) and then purged withnitrogen for 5 min. To this mixture was added[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride.DCM(0.091 g, 0.133 mmol), the vial was sealed and the mixture was heated at95° C. for 4 h. The cooled reaction mixture was partitioned with ethylacetate-saturated aqueous sodium bicarbonate and the organic phase wasseparated, washed with brine, dried over anhydrous magnesium sulfate andevaporated in vacuo. Chromatography of the residue on silica gel (ISCO,elution gradient of dichloromethane in hexane) gave 0.654 g (74%) of thetitle compound. LC (Method A): 2.966 min. HRMS(ESI): calcd forC₂₂H₃₄NO₃SSi [M+H]⁺ m/z 420.2029; found 420.2038. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.97-8.10 (m, 2H), 7.85-7.97 (m, 2H), 4.86 (s, 2H), 2.54(s, 3H), 1.62 (s, 9H), 0.94 (s, 9H), 0.14 (s, 6H).

45D. tert-Butyl 4-(4-(hydroxymethyl)-5-methylthiazol-2-yl)benzoate

The title compound was prepared according to the method described inExample 37D. LC (Method A): 2.225 min. HRMS(ESI): calcd for C₁₆H₂₀NO₃S[M+H]⁺ m/z 306.1164; found 306.1161. ¹H NMR (400 MHz, CDCl₃) δ ppm:7.99-8.07 (m, 2H), 7.87-7.99 (m, 2H), 4.74 (d, J=5.77 Hz, 2H), 2.50 (s,3H), 2.35 (t, J=5.77 Hz, 1H), 1.62 (s, 9H).

Example 45 tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)benzoate

The title compound was prepared according to the general Mitsunobucoupling procedure described in Example 36. LC (Method A): 2.761 min.HRMS(ESI): calcd for C₃₀H₂₉N₄O₆S₂[M+H]⁺ m/z 605.1529; found 605.1518. ¹HNMR (400 MHz, CDCl₃) δ ppm: 8.00-8.07 (m, 2H), 7.92-7.99 (m, 2H), 7.84(s, 1H), 7.06 (s, 1H), 6.69-6.73 (m, 1H), 6.55-6.59 (m, 1H), 5.34 (s,2H), 4.21 (s, 3H), 3.85 (s, 3H), 2.59 (s, 3H), 1.62 (s, 9H).

Example 464-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)benzoicacid

The title compound was prepared from Example 45 above according to thegeneral deprotection method described in Example 39D. LC (Method A):2.436 min. HRMS(ESI): calcd for C₂₆H₂₁N₄O₆S₂ [M+H]⁺ m/z 549.0903; found549.0898. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 13.07 (br s, 1H), 8.30 (s,1H), 7.92-8.01 (m, 4H), 6.87 (s, 1H), 6.76-6.79 (m, 1H), 6.60-6.64 (m,1H), 5.27 (s, 2H), 4.13 (s, 3H), 3.75 (s, 3H), 2.52 (s, 3H).

Example 474-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-(2,2,2-trifluoroethyl)benzamide

The title compound was prepared from Example 46 according to the generalamide coupling method described in Example 39. LC (Method A): 2.412 min.HRMS(ESI): calcd for C₂₈H₂₃F₃N₅O₅S₂ [M+H]⁺ m/z 630.1093; found 630.1092.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.99 (d, J=8.22 Hz, 2H), 7.76-7.88 (m,3H), 7.03 (s, 1H), 6.69 (s, 1H), 6.54 (s, 1H), 6.32 (t, J=6.46 Hz, 1H),5.31 (s, 2H), 4.06-4.22 (m, 5H), 3.83 (s, 3H), 2.57 (s, 3H).

Example 48N-(Cyanomethyl)-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-methylbenzamide

The title compound was prepared from Example 46 according to the generalamide coupling method described in Example 39. LC (Method A): 2.327 min.HRMS(ESI): calcd for C₂₉H₂₅N₆O₅S₂ [M+H]⁺ m/z 601.1328; found 601.1328.¹H NMR (400 MHz, CDCl₃) δ ppm: 8.00 (m, 2H), 7.84 (s, 1H), 7.52-7.59 (m,2H), 7.05 (s, 1H), 6.69-6.74 (m, 1H), 6.53-6.59 (m, 1H), 5.33 (s, 2H),4.48 (br s, 2H), 4.21 (s, 3H), 3.86 (s, 3H), 3.19 (s, 3H), 2.59 (s, 3H).

Example 494-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-methylbenzamide

The title compound was prepared from Example 46 according to the generalamide coupling method described in Example 39. LC (Method A): 2.364 min.HRMS(ESI): calcd for C₂₇H₂₄N₅O₅S₂ [M+H]⁺ m/z 562.1219; found 562.1215.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.98 (d, J=8.22 Hz, 2H), 7.78-7.86 (m,3H), 7.05 (s, 1H), 6.65-6.76 (m, 1H, 6.53-6.59 (m, 1H), 6.12-6.24 (m,1H), 5.33 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.05 (d, J=5.09 Hz, 3H),2.58 (s, 3H).

Preparation of Alcohols

The following additional alcohols were prepared according to theprocedures described in Examples 36 to 49.

HPLC Retention Calc. LCMS Time [M + H]⁺ [M + H]⁺ (Min)/ StructureFormula m/z m/z Method NMR

C₁₁H₈N₂OS 217.0   217.0   1.804/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.27(s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.57 (t, J= 7.8 Hz, 1H), 7.30 (s, 1H), 4.86 (d, J = 6.0 Hz, 2H), 2.26 (t, J = 6.0Hz, 1H).

C₁₂H₁₁NO₃S 250.0532 250.0566 1.813/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.80(d, J = 7.8 Hz, 1H), 7.72 (broad s, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.21(s, 1H), 7.17 (dd, J = 8.2, 2.3 Hz, 1H), 4.83 (d, J = 5.5 Hz, 2H), 2.34(s, 3H), 2.26 (br. t., 1H).

C₁₁H₈N₂OS 1.809/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.07 (d, J = 8.2 Hz,2H), 7.74 (d, J = 8.2 Hz, 2H), 7.33 (s, 1H), 4.87 (d, J = 5.9 Hz, 2H),2.22 (t, J = 5.9 Hz, 1H).

C₁₃H₁₄N₂O₂S 263.0849 263.0854 1.744/A ¹H NMR (400 MHz, CDCl₃) δ ppm:7.96- 8.04 (m, 2H), 7.43-7.54 (m, 2H), 7.22 (s, 1H), 4.84 (d, J = 6.0Hz, 2H), 3.15 (broad s, 3H), 3.02 (broad s, 3H), 2.33 (t, J = 6.0 Hz,1H).

C₉H₇FN₂OS 211.0336 211.032  1.633/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.32(d, J = 5.1 Hz, 1H), 7.70 (dt, J = 5.1, 1.7 Hz, 1H), 7.49 (t, J = 1.4Hz, 1H), 7.39 (s, 1H), 4.89 (d, J = 5.9 Hz, 2H), 2.24 (t, J = 5.9 Hz,1H).

C₁₃H₁₃NO₃S 264.0689 264.0687 1.928/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.95(d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.20 (s, 1H), 5.15 (s,2H), 4.84 (d, J = 6.0 Hz, 2H), 2.29 (t, J = 6.0 Hz, 1H), 2.14 (s, 3H).

C₁₁H₁₀N₂O₂S 235.0536 235.0537 1.528/A ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.08 (br. s., 1H), 7.95-8.02 (m, 4H), 7.55 (s, 1H), 7.46 (br. s., 1H),5.41 (t, J = 5.3 Hz, 1H), 4.64 (d, J = 5.3 Hz, 2H).

C₉H₇FN₂OS 1.357/A ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.78 (d, J = 2.7 Hz,1H), 8.43-8.52 (m, 1H), 7.57 (d, J = 1.1 Hz, 1H), 7.33 (dd, J = 8.6, 2.3Hz, 1H), 5.43 (br. t., 1H), 4.64 (broad d, 2H).

C₁₀H₁₀N₂OS 207.0587 207.0593 0.853/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 9.05(d, J = 2.3 Hz, 1H), 8.12 (dd, J = 8.2, 2.3 Hz, 1H), 7.24 (d, J = 8.2Hz, 1H), 7.26 (s, 1H), 4.85 (d, J = 5.4 Hz, 2H), 2.62 (s, 3H), 2.38 (t,J = 5.4 Hz, 1H).

C₉H₈N₂OS 193.043  207.0437 0.710/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.67-8.77 (m, 2H), 7.77-7.87 (m, 2H), 7.35 (s, 1H), 4.88 (d, J = 5.9 Hz, 2H),2.32 (t, J = 5.9 Hz, 1H).

C₉H₇FN₂OS 1.412/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.67- 8.79 (m, 1H),8.28 (broad d, J = 5.1 Hz, 1H), 7.40 (s, 1H), 7.31-7.38 (m, 1H), 4.88(d, J = 6.0 Hz, 2H), 2.23 (t, J = 6.0 Hz, 1H).

C₁₀H₁₀N₂O₂S 223.0536 223.053  1.168/A ¹H NMR (400 MHz, CDCl₃) δ ppm:8.74 (d, J = 1.6 Hz, 1H), 8.38 (d, J = 3.1 Hz, 1H), 7.77-7.80 (m, 1H),7.28 (s, 1H), 4.87 (d, J = 5.9 Hz, 2H), 3.95 (s, 3H), 2.27 (t, J = 5.9Hz, 1H).

C₉H₇ClN₂OS 227.004  227.0036 1.529/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.94(d, J =2.6 Hz, 1H), 8.21 (dd, J = 8.7, 2.6 Hz, 1H), 7.43 (d, J = 8.7 Hz,1H), 7.30 (s, 1H), 4.86 (d, J = 5.9, Hz, 2H), 2.21 (t, J = 5.9 Hz, 1H).

C₁₁H₁₁NO₃S₂ 270.0252 270.026  1.337/A ¹H NMR (400 MHz, CDCl₃) δ ppm:8.12- 8.19 (m, 2H), 7.99-8.06 (m, 2H), 7.34 (s, 1H), 4.88 (d, J = 5.9Hz, 1H), 3.10 (s, 3H), 2.24 (t, J = 5.9 Hz, 1H).

C₉H₈N₂OS 193.043  193.0445 0.836/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 9.18(d, J = 2.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.22-8.27 (m, 1H),7.40 (dd, J = 8.0, 4.8 Hz, 1H), 7.28 (s, 1H), 4.87 (d, J = 5.9 Hz, 2H),2.37 (t, J = 5.9 Hz, 1H).

C₁₄H₁₆N₂O₂S 277.1005 277.1013 1.845/A ¹H NMR (400 MHz, CDCl₃) δ ppm:7.92 (~ d, J = 8.2 Hz, 2H), 7.48 ((~ d, J = 8.2 Hz, 2H), 4.73 (d, J =5.9 Hz, 2H), 3.13 (br. s., 3H), 3.01 (br. s., 3H), 2.49 (s, 3H), 2.48(t, J = 5.9 Hz, 1H).

C₁₂H₁₂N₂O₂S 249.0692 249.0692 1.658/A ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.06 (br. s., 1H), 7.90-8.00 (m, 4H), 7.44 (br. s., 1H), 5.14 (t, J =5.5 Hz, 1H), 4.55 (d, J = 5.5 Hz, 2H), 2.5 (Me under DMSO).

C₁₀H₉FN₂OS 225.0492 225.0494 1.551/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.29(d, J = 5.5 Hz, 1H), 7.64 (d, J = 5.5 Hz, 1H), 7.41 (s, 1H), 4.76 (d, J= 5.9 Hz, 2H), 2.54 (s, 3H), 2.30 (t, J = 5.9 Hz, 1H).

C₁₄H₁₅NO₃S 278.0845 278.0849 1.996/A ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.90(s, 1H), 7.80-7.84 (m, 1H), 7.37-7.46 (m, 2H), 5.16 (s, 2H), 4.73 (d, J= 5.9 Hz, 2H), 2.48 (s, 3H), 2.43 (t, J = 5.9 Hz, 1H), 2.14 (s, 3H).

Examples 50 to 82

The following additional Examples have been prepared, isolated andcharacterized using the methods disclosed above.

HPLC Re- tention Calc. Time LCMS [M + H]⁺ (Min)/ [M + H]⁺ Ex. StructureFormula m/z Method m/z NMR 50

C₂₂H₂₂N₄O₄S₂ 471.1155 2.574/A 471.1236 ¹H NMR (CDCl₃) δ ppm: 7.85 (s,1H), 7.23 (s, 1H), 7.09 (s, 1H), 6.71 (br. d, 1H), 6.43 (d, J = 2.0 Hz,1H), 5.31 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 2.90 (d, J = 7.4 Hz, 2H),2.10- 2.18 (m, 1H), 1.02 (d, J = 6.7 Hz, 6H) 51

C₂₄H₂₅N₅O₅S₂ 528.137  2.572/A 528.1415 ¹H NMR (CDCl₃) δ ppm: 7.85 (s,1H), 7.10 (s, 1H), 6.70 (br. d, 1H), 6.62 (s, 1H), 6.43 (d, J = 2.0 Hz,1H), 5.12 (s, 2H), 4.21 (s, 3H), 3.84 (s, 3H), 3.70- 3.82 (m, 4H), 2.76(dd, J = 12.9, 11.0 Hz, 2H), 1.27 (d, J = 6.3 Hz, 6H) 52

C₂₁H₂₀N₄O₄S₂ 457.0999 2.517/A 457.1057 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.85 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 6.71 (br. d, 1H), 6.44 (d, J =2.0 Hz, 1H), 5.30 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.3- 3.4 (m, 1H),1.44 (d, J = 7.0 Hz, 6H) 53

C₂₂H₂₁N₅O₄S₃ 516.0828 2.481/A 516.0887 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.85 (s, 1H), 7.10 (s, 1H), 6.70 (br. d, 1H), 6.61 (s, 1H), 6.44 (d, J =1.6 Hz, 1H), 5.10 (s, 2H), 4.21 (s, 3H), 3.85-3.90 (m, 4H), 3.85 (s,3H), 2.68-2.79 (m, 4H) 54

C₂₂H₂₁N₅O₆S₃ 548.0727 2.47/A 548.0744 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.37 (s, 1H), 7.04 (s, 1H), 6.98 (d, J = 0.8 Hz, 1H), 6.83 (br. d, 1H),6.57 (d, J = 2.0 Hz, 1H), 5.07 (s, 2H), 4.20 (s, 3H), 3.89-3.99 (m, 4H),3.80 (s, 3H), 3.21-3.28 (m, 4H). 55

C₂₂H₂₁N₅O₅S₃ 532.0778 2.526/A 532.0839 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.37 (s, 1H), 6.99 (s, 1H), 6.97 (s, 1H), 6.82 (br. d, 1H), 6.58 (d, J =2.0 Hz, 1H), 5.07 (s, 2H), 4.20 (s, 3H), 3.82-3.96 (m, 4H), 3.80 (s,3H), 2.91-3.06 (m, 2H), 2.75-2.85 (m, 2H). 56

C₂₃H₂₃N₅O₅S₂ 514.1213 2.411/A 514.1258 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.86 (s, 1H), 7.09 (s, 1H), 6.72 (br. s, 1H), 6.60 (s, 1H), 6.49 (br. s,1H), 5.37 (s, 2H), 4.22 (s, 3H), 3.90- 4.0 (m., 4H), 3.85 (s, 3H),3.78-3.88 (m, 4H), 2.09-2.21 (m, 2H). 57

C₂₅H₁₈N₄O₆S₂ 535.0741 2.681/A 535.0766 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.87 (br. s., 1H), 7.49-7.62 (m, 3H), 7.39 (br. s., 1H), 6.90 (d, J =8.2 Hz, 1H), 6.71 (br. s, 1H), 6.50 (br. s, 1H), 6.06 (s, 2H), 5.42 (s,2H), 4.27 (s, 3H), 3.86 (s, 3H). 58

C₂₁H₁₇F₃N₄O₄S₂ 511.0716 2.499/A 511.0773 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.86 (s, 1H), 7.32 (d, J = 0.8 Hz, 2H), 6.70 (br. d, 1H), 6.44 (d, J =2.0 Hz, 1H), 5.28 (br. s, 2H), 4.27 (s, 3H), 3.86 (s, 3H), 3.26-3.35 (m,2H), 2.63-2.79 (m, 2H). 59

C₂₃H₂₂N₄O₄S₃ 515.0876 2.613/A 515.091  ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.37 (s, 1H), 7.71 (s, 1H), 6.98 (s, 1H), 6.84 (br. d, 1H), 6.61 (d, J =2.0 Hz, 1H), 5.27 (s, 2H), 4.21 (s, 3H), 3.81 (s, 3H), 3.10-3.18 (m,1H), 2.75-2.86 (m, 2H), 2.63-2.74 (m, 2H), 2.30-2.42 (m, 2H), 1.72-1.88(m, 2H). 60

C₂₃H₂₂N₄O₄S₂ 483.1155 2.549/A 483.1191 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.85 (s, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 6.71 (br. d, 1H), 6.43 (d, J =1.5 Hz, 1H), 5.30 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.09-3.17 (m,2H), 1.68-1.78 (m, 2H), 0.74-0.88 (m, 1H), 0.44-0.52 (m, 2H), 0.06-0.15(m, 2H). 61

C₂₅H₁₇N₅O₄S₂ 516.0795 2.561/A 516.0823 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.29 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 7.8Hz, 1H), 7.59 (br. t, 1H), 7.47 (s, 1H), 7.12 (s, 1H), 6.73 (br. d, 1H),6.47 (d, J = 2.0 Hz, 1H), 5.41 (s, 2H), 4.22 (s, 3H), 3.86 (s, 3H). 62

C₂₆H₂₀N₄O₆S₂ 549.0897 2.538/A 549.0534 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.86 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.74 (br. s, 1H), 7.47 (br. t, J= 7.8 Hz, 1H), 7.39 (s, 1H), 7.18 (dd, J = 7.8, 1.6 Hz, 1H), 7.12 (s,1H), 6.73 (br. d, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.39 (s, 2H), 4.22 (s,3H), 3.85 (s, 3H), 2.34 (s, 3H). 63

C₂₄H₁₈N₄O₅S₂ 507.0729 2.459/A 507.0831 ¹H NMR (400 MHz, CDCl₃) δ ppm:9.77 (s, 1H), 8.37 (s, 1H), 7.86 (s, 1H), 7.35-7.41 (m, 2H), 7.27-7.34(m, 1H), 7.03 (s, 1H), 6.88-6.92 (m, 1H), 6.85 (br. d, 1H), 6.65 (d, J =1.6 Hz, 1H), 5.36 (s, 2H), 4.20 (s, 3H), 3.82 (s, 3H). 64

C₂₅H₁₇N₅O₄S₂ 516.0795 2.607/A 516.0805 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.09 (broad d, J = 8.6 Hz, 2H), 7.86 (s, 1H), 7.75 (br. d, J = 8.6 Hz,2H), 7.50 (s, 1H), 7.11 (s, 1H), 6.73 (br. d, 1H), 6.46 (d, J = 2.0 Hz,1H), 5.41 (s, 2H), 4.22 (s, 3H), 3.86 (s, 3H). 65

C₂₇H₂₃N₅O₅S₂ 562.1213 2.592/A 562.1235 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.99- 8.06 (m, 2H), 7.86 (s, 1H), 7.47-7.55 (m, 2H), 7.41 (s, 1H), 7.12(s, 1H), 6.73 (br. d, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.40 (s, 2H), 4.22(s, 3H), 3.85 (s, 3H), 3.15 (br. s., 3H), 3.04 (br. s, 3H). 66

C₂₈H₂₅N₅O₅S₂ 576.137  2.571/A 576.1386 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.95 (d, J = 8.2 Hz, 2H), 7.84 (s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.05(s, 1H), 6.71 (br. s, 1H), 6.56 (d, J = 1.2 Hz, 1H), 5.33 (s, 2H), 4.20(s, 3H), 3.85 (s, 3H), 3.13 (br. s., 3H), 3.02 (br. s., 3H), 2.58 (s,3H). 67

C₂₃H₁₆NFN₅O₄S₂ 510.0701 2.602/A 510.0739 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.33 (d, J = 5.1 Hz, 1H), 7.86 (s, 1H), 7.73 (d, J = 5.1 Hz, 1H), 7.56(s, 1H), 7.51 (s, 1H), 7.12 (s, 1H), 6.73 (br. d, 1H), 6.46 (d, J = 1.2Hz, 1H), 5.42 (s, 2H), 4.22 (s, 3H), 3.86 (s, 3H). 68

C₂₇H₂₂N₄O₆S₂ 563.1054 2.634/A 563.1053 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.97 (d, J = 8.6 Hz, 2H), 7.86 (s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.39(s, 1H), 7.12 (s, 1H), 6.73 (br. d, 1H), 6.48 (d, J = 1.6 Hz, 1H), 5.40(s, 2H), 5.16 (s, 2H), 4.22 (s, 3H), 3.85 (s, 3H), 2.14 (s, 3H). 69

C₂₅H₂₀N₄O₅S₂ 521.0948 2.500/A 521.0948 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.36 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.44 (d, J = 8.4Hz, 2H), 7.02 (s, 1H), 6.84 (br. d, 1H), 6.64 (d, J = 2.0 Hz, 1H), 5.36(s, 2H), 5.31 (t, J = 5.6 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 4.19 (s,3H), 3.81 (s, 3H). 70

C₂₆H₂₁N₅O₅S₂ 548.1057 2.445/A 548.1054 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.37 (s, 1H), 8.07 (broad s, 1H), 7.93- 8.01 (m, 4H), 7.46 (br. s., 1H),6.93 (s, 1H), 6.85 (broad d, 1H), 6.69 (d, J = 2.0 Hz, 1H), 5.32 (s,2H), 4.19 (s, 3H), 3.82 (s, 3H), 2.58 (s, 3H). 71

C₂₄H₁₈FN₅O₄S₂ 524.0857 2.382/A 524.0882 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.29 (d, J = 5.5 Hz, 1H), 7.84 (s, 1H), 7.65-7.68 (m, 1H), 7.44 (br. s,1H), 7.05 (s, 1H), 6.72 (br. d, 1H), 6.55 (d, J = 2.0 Hz, 1H), 5.35 (s,2H), 4.21 (s, 3H), 3.86 (s, 3H), 2.62 (s, 3H). 72

C₂₅H₁₉BrN₅O₅S₂ 534.09  2.457/A 534.0902 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.37 (s, 1H), 8.09 (br. s., 1H), 7.98-8.07 (m, 4H), 7.97 (s, 1H), 7.48(br. s., 1H), 7.03 (s, 1H), 6.85 (broad d, 1H), 6.66 (d, J = 2.0 Hz,1H), 5.39 (s, 2H), 4.20 (s, 3H), 3.82 (s, 3H). 73

C₂₃H₁₆FN₅O₄S₂ 510.0701 2.347/A 510.0706 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.80 (d, J = 2.7 Hz, 1H), 8.39 (ddd, J = 8.6, 7.4, 2.7 Hz, 1H), 7.86 (s,1H), 7.44 (s, 1H), 7.12 (br. s, 1H), 7.05 (dd, J = 8.6, 2.7 Hz, 1H),6.74 (br. d, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.40 (s, 2H), 4.22 (s, 3H),3.86 (s, 3H). 74

C₂₄H₁₉N₅O₄S₂ 506.0951 2.176/A 506.0952 ¹H NMR (400 MHz, CDCl₃) δ ppm:9.06 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 8.0, 2.5 Hz, 1H), 7.86 (s, 1H),7.41 (s, 1H), 7.26 (d, 1H), 7.12 (s, 1H), 6.73 (br. d, 1H), 6.48 (d, J =2.0 Hz, 1H), 5.41 (s, 2H), 4.22 (s, 3H), 3.85 (s, 3H), 2.63 (s, 3H). 75

C₂₃H₁₇N₅O₄S₂ 492.0795 2.143/A 492.0796 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.70- 8.77 (m, 2H), 7.86 (s, 1H), 7.82-7.86 (m, 2H), 7.52 (br. s, 1H),7.12 (s, 1H), 6.73 (br. d, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.42 (s, 2H),4.22 (s, 3H), 3.86 (s, 3H). 76

C₂₈H₂₄N₄O₆S₂ 577.121  2.660/A 577.1213 ¹H NMR (400 MHz, CDCl₃) δ ppm:7.93 (s, 1H), 7.86 (broad d, J = 7.4 Hz, 1H), 7.84 (s, 1H), 7.37-7.47(m, 2H), 7.06 (s, 1H), 6.71 (broad d, 1H), 6.57 (d, J = 1.6 Hz, 1H),5.33 (s, 2H), 5.17 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 2.57 (s, 3H),2.14 (s, 3H). 77

C₂₆H₂₂N₄O₅S₂ 535.1104 2.535/A 535.1102 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.37 (s, 1H), 7.88 (s, 1H), 7.75 (broad d, J = 7.8 Hz, 1H), 7.37-7.48(m, 2H), 6.93 (s, 1H), 6.84 (broad d, 1H), 6.69 (d, J = 1.6 Hz, 1H),5.33 (t, J = 5.9 Hz, 1H), 5.31 (s, 2H), 4.57 (d, J = 5.9 Hz, 2H), 4.19(s, 3H), 3.82 (s, 3H), 2.56 (s, 3H). 78

C₂₃H₁₆FN₅O₄S₂ 510.0701 2.452/A 510.0691 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.76 (ddd, J = 9.5, 7.5, 2.2 Hz, 1H), 8.24-8.33 (m, 1H), 7.86 (s, 1H),7.57 (br. s, 1H), 7.32- 7.41 (m, 1H), 7.12 (br. s, 1H), 6.73 (br. d,1H), 6.47 (d, J = 2.0 Hz, 1H), 5.42 (s, 2H), 4.22 (s, 3H), 3.86 (s, 3H).79

C₂₄H₁₉N₅O₅S₂ 522.09  2.383/A 522.0874 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.75 (s, 1H), 8.38 (d, J = 2.7 Hz, 1H), 7.86 (s, 1H), 7.82 (br. s, 1H),7.45 (s, 1H), 7.12 (s, 1H), 6.73 (br. d, 1H), 6.48 (d, J = 1.6 Hz, 1H),5.41 (s, 2H), 4.22 (s, 3H), 3.96 (s, 3H), 3.86 (s, 3H). 80

C₂₃H₁₆ClN₅O₄S₂ 526.0405 2.429/A 526.0402 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.96 (d, J = 2.2 Hz, 1H), 8.24 (dd, J = 8.7, 2.2 Hz, 1H), 7.86 (s, 1H),7.47 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.11 (s, 1H), 6.73 (br. d, 1H),6.47 (d, J = 2.0 Hz, 1H), 5.40 (s, 2H), 4.22 (s, 3H), 3.86 (s, 3H). 81

C₂₅H₂₀N₄O₆S₃ 569.0618 2.310/A 569.0624 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.14- 8.22 (m, 2H), 8.00- 8.07 (m, 2H), 7.86 (s, 1H), 7.51 (s, 1H), 7.12(s, 1H), 6.73 (br. d, 1H), 6.47 (d, J = 1.6 Hz, 1H), 5.42 (s, 2H), 4.22(s, 3H), 3.86 (s, 3H), 3.11 (s, 3H). 82

C₂₃H₁₇N₅O₄S₂ 492.0795 2.307/A 492.0798 ¹H NMR (400 MHz, CDCl₃) δ ppm:9.16- 9.24 (m, 1H), 8.68 (dd, J = 4.7, 1.6 Hz, 1H), 8.25-8.30 (m, 1H),7.86 (s, 1H), 7.46 (s, 1H), 7.38-7.44 (m, 1H), 7.12 (s, 1H), 6.73 (br.d, 1H), 6.48 (d, J = 2.0 Hz, 1H), 5.42 (s, 2H), 4.22 (s, 3H), 3.86 (s,3H).

Example 832-Methoxy-6-(6-methoxy-4-(1-(2-phenylthiazol-4-yl)ethoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

83A. 2-Phenylthiazole-4-carboxylic acid

A solution of ethyl 2-phenylthiazole-4-carboxylate (Example 4B, 3.046 g,13.06 mmol) in methanol (20 mL) was treated with a solution of NaOH(1.044 g, 26.1 mmol) in water (10 mL) added dropwise over 2 min and theresulting solution was stirred at room temperature for 1 h. The methanolwas then evaporated under reduced pressure and the residual paste wasdiluted with a mixture of water (30 mL) and ethyl acetate (200 mL). ThepH was adjusted to ˜3 with concentrated hydrochloric acid, the organicphase was separated and the aqueous phase was re-extracted with ethylacetate (2×150 mL). The combined organic extract was washed with brine(3×35 mL) and dried over anhydrous magnesium sulfate. Afterconcentration of the solvent under reduced pressure, the solid residueobtained was dried in vacuo for 18 h to yield 2.629 g (98%) of the titlecompound as a white crystalline solid. LC (Method A): 1.842 min.HRMS(ESI) Anal.Calcd for C₁₀H₈NO₂S [M+H]⁺ m/z 206.027; found 206.0266.¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.30 (s, 1H), 7.94-8.05 (m, 2H), 7.4-7.55(m, 3H).

83B. N-Methoxy-N-methyl-2-phenylthiazole-4-carboxamide

A mixture of 2-phenylthiazole-4-carboxylic acid (1.00 g, 4.87 mmol) indichloromethane (20 mL) was treated with oxalyl chloride (1.237 g, 9.75mmol) and a drop of N,N-dimethylformamide and the resulting mixture wasstirred at 22° C. for 4 h. The solvent was evaporated under reducedpressure and the residual solid was co-evaporated with toluene (10 mL).This solid was diluted with dichloromethane (10 mL) and added dropwiseover 2 min to an ice-cold mixture of N,O-dimethylhydroxylaminehydrochloride (0.713 g, 7.31 mmol) and triethylamine (2.03 mL, 14.62mmol) in dichloromethane (20 mL). The cooling bath was then removed andthe mixture with a white precipitate was stirred at room temperature for1 h. The reaction mixture was quenched by addition of saturated aqueoussodium bicarbonate (30 mL) and dichloromethane (200 mL). The organicphase was washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo to give a clear oil. This oil was chromatographedon silica gel (elution toluene-ethyl acetate; 8:2 to 7:3) to give 1.054g (87%) of the title compound as a clear oil. LC (Method A): 2.022 min.HRMS(ESI) Anal.Calcd for C₁₂H₁₃N₂O₂S [M+H]⁺ m/z 249.0692; found249.0694. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.03 (s, 1H), 7.91-8.01 (m,2H), 7.39-7.55 (m, 3H), 3.90 (s, 3H), 3.51 (br s, 3H).

83C. 1-(2-Phenylthiazol-4-yl)ethanone

A solution of N-methoxy-N-methyl-2-phenylthiazole-4-carboxamide (1.00 g,4.03 mmol) in dry tetrahydrofuran (20 mL) at 0° C. was treated withmethylmagnesium bromide (1 M in butyl ether, 6.0 mL, 6.0 mmol) dropwiseover 2 min. The resulting pale yellow solution was stirred at 0° C. for30 min and then the reaction mixture was quenched by addition to amixture of ice (ca. 200 g) and concentrated hydrochloric acid (2 mL).The aqueous phase was extracted with ethyl acetate and the organicextract was washed with saturated aqueous sodium bicarbonate and brine.The organic phase was dried over anhydrous magnesium sulfate andconcentrated in vacuo to give a white solid. This solid waschromatographed on silica gel (elution with 0-5% ethyl acetate-toluene)to give 0.806 g (98%) of the title compound as colorless prisms. LC(Method A): 2.017 min. HRMS(ESI) Anal.Calcd for C₁₁H₁₀NOS [M+H]⁺ m/z204.0478; found 204.0484. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.14 (d, J=1.6Hz, 1H), 7.95-8.05 (m, 2H), 7.43-7.57 (m, 3H), 2.76 (d, J=1.6 Hz, 3H).

83D. 1-(2-Phenylthiazol-4-yl)ethanol

A solution of 1-(2-phenylthiazol-4-yl)ethanone (0.410 g, 2.017 mmol) indry tetrahydrofuran (5 mL) was cooled to 0° C. and treated with sodiumborohydride (0.114 g, 3.03 mmol), followed by methanol (0.040 mL, 1.0mmol). The resulting purple mixture was stirred at 0° C. for 15 min andthen at 23° C. for 5 h. The mixture was re-cooled in ice and treateddropwise with 1 mL of 50% aqueous acetic. The mixture was thenpartitioned between ethyl acetate (200 mL) and saturated aqueous sodiumbicarbonate. The organic phase was separated, washed with saturatedsodium bicarbonate and brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure to give a yellow syrup. This materialwas chromatographed on silica gel (elution with 20-40% ethylacetate-toluene) to give 0.392 g (95%) of the title material as a paleyellow syrup. LC (Method A): 1.874 min. HRMS(ESI) Anal.Calcd forC₁₁H₁₂NOS [M+H]⁺ m/z 206.0634; found 206.0638. ¹H NMR (CDCl₃, 400 MHz) δppm: 7.9-8.0 (m, 2H), 7.4-7.5 (m, 3H), 7.12 (s, 1H), 5.05 (q, J=6.3 Hz,1H), 2.87 (br s, 1H), 1.63 (d, J=6.3 Hz, 3H).

Example 832-Methoxy-6-(6-methoxy-4-(1-(2-phenylthiazol-4-yl)ethoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.080 g, 0.252 mmol) and 1-(2-phenylthiazol-4-yl)ethanol(0.062 g, 0.303 mmol) in dry tetrahydrofuran (10 mL) was treated at 22°C. and under nitrogen with tri-n-butylphosphine (0.157 mL, 0.63 mmol)added in one portion, followed by a solution of1,1′-(azodicarbonyl)dipiperidine (0.083 g, 0.328 mmol) intetrahydrofuran (4 mL) added dropwise over 30 min. After another 2 h at22° C., the reaction mixture was partitioned between dichloromethane andsaturated sodium bicarbonate. The organic phase was washed with brine,dried over anhydrous magnesium sulfate and concentrated in vacuo to givea glassy residue. Chromatography on silica gel (elution gradient ofethyl acetate in dichloromethane) gave 0.078 g (61%) of the titlecompound as a white solid, after trituration with acetonitrile. LC(Method A): 2.596 min. HRMS(ESI) Anal.Calcd for C₂₅H₂₀N₄O₅S₂ [M+H]⁺ m/z505.0999; found 505.1001. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.95-8.0 (m,2H), 7.86 (s, 1H), 7.40-7.50 (m, 3H), 7.23 (s, 1H), 7.14 (s, 1H), 6.68(br d, 1H), 6.39 (d, J=2.0 Hz, 1H), 5.73 (q, J=6.5 Hz, 1H), 4.22 (s,3H), 3.79 (s, 3H), 1.82 (d, J=6.5 Hz, 3H).

Example 844-(5-Chloro-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b]thiadiazol-6-yl)benzofuran-4-yl)oxy)thiazol-2-yl)morpholine

84A. Methyl and Ethyl-2-morpholinothiazole-4-carboxylate

A solution of morpholine (3.0 mL, 34.2 mmol) in EtOH (50 mL) was treatedwith methyl 2-bromothiazole-4-carboxylate (1.65 g, 7.43 mmol) and DIEA(6.8 mL, 39.4 mmol) and the resulting mixture was refluxed for 18 hunder N₂. The reaction mixture was then concentrated under reducedpressure and the residue was purified on the ISCO using a REDISEP® 24 gcolumn (0 to 30% EtOAc-DCM) to give the product (1.22 g, 72%; mixture ofmethyl and ethyl esters) as a yellow oil. This mixture was used as suchin the next step. LCMS (APCI): calcd for C₁₀H₁₅N₂O₃S [M+H]⁺ m/z 277.03,found 277.1; LCMS (APCI): calcd for C₉H₁₃N₂O₃S [M+H]⁺ m/z 229.06, found229.1.

84B. 5-Chloro-2-morpholinothiazole-4-carboxylic acid ethyl ester and5-Chloro-2-morpholinothiazole-4-carboxylic acid methyl ester

A mixture of 2-morpholinothiazole-4-carboxylic acid ethyl and methylester (1.22 g, 5.04 mmol) in a mixture of DCM-CHCl₃-acetic acid (1:1:1,9 mL) was treated at 22° C. with N-chlorosuccinimide (0.807 g, 6.04mmol). The resulting mixture was stirred at room temperature for 2 h,then more NCS was added (0.050 g) and the mixture was stirred at 40° C.for 18 h. CELITE® was then added and the mixture was concentrated. DCMwas added, followed by saturated aqueous NaHCO₃ and the organic layerwas separated, washed with brine, dried over MgSO₄ and evaporated todryness. The residue was purified on the ISCO using a REDISEP® 24 gcolumn (0 to 30% EtOAc-DCM) to give the title esters as a white solid(0.746 g, 54%). This mixture was used as such in the next step. LCMS(APCI): calcd for C₁₀H₁₄ClN₂O₃S [M+H]⁺ m/z 277.03, found 277.1; LCMS(APCI): calcd for C₉H₁₂ClN₂O₃S [M+H]⁺ m/z 263.02, found 263.0. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 4.38 (q, J=7.0 Hz, 1H), 3.91 (s, 1H), 3.76-3.83(m, 4H), 3.40-3.49 (m, 4H), 1.40 (t, J=7.0 Hz, 2H).

84C. (5-Chloro-2-morpholinothiazol-4-yl)methanol

A mixture of 2-morpholinothiazole-4-carboxylic acid ethyl and methylesters (0.746 g, 2.70 mmol) in Et₂O (50 mL) was cooled at −78° C. andtreated with LAH (0.307 g, 8.09 mmol). The cooling bath was then removedand the resulting mixture was stirred for 2.5 h at room temperature. Thereaction mixture was re-cooled at −78° C. and quenched by the dropwiseaddition of ethyl acetate (5 mL) over 5 min. After 10 min, water (8.0mL) was added dropwise over 5 min then an aqueous solution of 1 N NaOH(8.5 mL) and finally water (10 mL). The cooling bath was removed and theheterogeneous mixture was stirred at room temperature until it becamewhite (ca. 30 min). The suspension was then filtered and the filter-cakewashed with diethyl ether (10 mL). The combined filtrate was washed withbrine and dried over anhydrous magnesium sulfate. Evaporation gave thedesired compound as an off-white solid (0.249 g, 39%). This material wasused as such in the next step. LCMS (APCI): calcd for C₈H₁₂ClN₂O₂S[M+H]⁺ m/z 235.02, found 235.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.52 (d,J=5.7 Hz, 2H), 3.76-3.84 (m, 4H), 3.37-3.44 (m, 4H), 2.32 (t, J=5.7 Hz,1H).

Example 844-(5-Chloro-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b]thiadiazol-6-yl)benzofuran-4-yl)oxy)thiazol-2-yl)morpholine

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.070 g, 0.22 mmol) and(5-chloro-2-morpholinothiazol-4-yl)methanol (0.057 g, 0.24 mmol) wereadded to a 25 mL round-bottom flask which was then flushed with N₂. Thendry THF (4 mL) and tri-n-butylphosphine (0.14 mL, 0.55 mmol) were addedand the reaction mixture was treated dropwise with a solution of 1,1′(azodicarbonyl)dipiperidine (0.139 g, 0.55 mmol) in dry THF (3.5 mL)over 1 h. The resulting beige suspension was stirred for an additional 2h at room temperature and then it was diluted with EtOAc, washed withNaHCO₃ and brine, dried over MgSO₄ and evaporated to dryness. Theresidue was purified on the ISCO using a REDISEP® 4 g column (0 to 40%EtOAc-DCM). The obtained solid was suspended in MeOH, sonicated,filtered and dried in vacuo to give the title compound (0.082 g, 70%) asa white solid. LC (Method C): 2.366 min. HRMS(ESI): calcd forC₂₂H₂₁ClN₅O₅S₂ [M+H]⁺ m/z 534.059, found 534.0719. ¹H NMR (CDCl₃, 400MHz) δ ppm: 7.83 (s, 1H), 7.08 (s, 1H), 6.70 (d, J=1.6 Hz, 1H), 6.51 (d,J=1.6 Hz, 1H), 5.05 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.77-3.83 (m,4H), 3.39-3.46 (m, 4H).

Example 856-(4-((5-Chloro-2-phenylthiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoximidazo[2,1-b][1,3,4]thiadiazole

85A. Ethyl 2-phenylthiazole-4-carboxylate

A solution of benzothioamide (3.00 g, 21.87 mmol) in EtOH (70 mL) wastreated dropwise with ethyl bromopyruvate (5.10 g, 26.2 mmol) andstirred at room temperature for 30 min before being heated at reflux for1.5 h. The cooled mixture was diluted with ethyl acetate (200 mL),washed (aqueous NaHCO₃, brine), dried over anhydrous MgSO₄ andevaporated. The residue was purified on the ISCO using a REDISEP® 80 gcolumn (10 to 20% EtOAc-hexane) to give the title compound (4.82 g, 94%)as a yellow oil. LCMS (APCI): calcd for C₁₂H₁₂NO₂S [M+H]⁺ m/z 234.05,found 234.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.14-8.19 (m, 1H), 7.98-8.07(m, 2H), 7.41-7.51 (m, 3H), 4.46 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz,3H).

85B. 5-Chloro-2-phenylthiazole-4-carboxylic acid ethyl ester

Ethyl 2-phenylthiazole-4-carboxylate (0.300 g, 1.29 mmol) was treatedaccording to the method described in Example 84B above. The cruderesidue was purified on the ISCO using a REDISEP® 24 g column (0 to 30%EtOAc-hexane) to give the title material as a colorless oil (0.066 g,19%). LCMS (APCI): calcd for C₁₂H₁₁ClNO₂S [M+H]⁺ m/z 268.01, found268.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.87-7.94 (m, 2H), 7.42-7.50 (m,3H), 4.48 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H).

85C. (5-Chloro-2-phenylthiazol-4-yl)methanol

5-Chloro-2-phenylthiazole-4-carboxylic acid ethyl ester (0.066 g, 0.25mmol) was reduced according to the method described in Example 5B toyield the title compound (0.048 g, 86%) as a pale yellow solid. LCMS(APCI): calcd for C₁₀H₉ClNOS [M+H]⁺ m/z 226.00, found 226.0. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.86 (dd, J=6.5, 2.2 Hz, 2H), 7.39-7.50 (m, 3H),4.77 (s, 2H), 2.39 (br s, 1H).

Example 85 6-(4-((5-Chloro-2-phenylthiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.058 g, 0.18 mmol) and(5-chloro-2-phenylthiazol-4-yl)methanol (0.041 g, 0.18 mmol) werereacted as described in Example 36. The crude residue was purified onthe ISCO using a REDISEP® Gold 12 g column (5 to 20% EtOAc-DCM) and theobtained product was triturated with CH₃CN-MeOH. The resulting solid wasre-purified on the ISCO using a REDISEP® 4 g column (0 to 10% EtOAc-DCM)to give the pure title compound as a pale yellow solid (0.048 g, 50%).LC (Method C): 2.569 min. LCMS (APCI): calcd for C₂₄H₁₈ClN₄O₄S₂ [M+H]⁺m/z 525.04, found 525.10. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.86 (dt,J=3.8, 3.0 Hz, 2H), 7.81 (s, 1H), 7.39-7.46 (m, 3H), 7.06 (s, 1H), 6.70(s, 1H), 6.55 (d, J=2.0 Hz, 1H), 5.28 (s, 2H), 4.18 (s, 3H), 3.84 (s,3H).

Example 864-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)morpholine

86A. Methyl 2-morpholino-5-(trifluoromethyl)thiazole-4-carboxylate

This product was prepared adapting the methodology described by Nagib,D. A. et al., (Nature, 480:224 (2011)). Thus, a 50 mL round-bottomedflask was charged with methyl 2-morpholinothiazole-4-carboxylate (0.200g, 0.876 mmol) [cf. Example 84A], potassium phosphate dibasic (1.831 g,10.51 mmol) [previously dried at 105° C. in vacuo overnight] anddichlorotris(1,10-phenanthroline)-ruthenium(II) hydrate (0.030 g, 0.04mmol) and the mixture was maintained under vacuum for 10 min. The flaskwas then flushed with nitrogen, charged with acetonitrile (10 mL),degassed under light vacuum for 2 min and then again flushed withnitrogen. Then trifluoromethanesulfonyl chloride (0.742 mL, 7.01 mmol)was added all at once and the orange suspension was stirred andirradiated with a 13 W Globe fluorescent light bulb for 24 h. Thereaction mixture was then quenched by addition to a mixture of ethylacetate (200 mL) and water (50 mL). The organic phase was separated,washed successively with saturated aqueous sodium bicarbonate (20 mL)and brine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The obtained pale yellow oily residue waschromatographed on silica gel (elution with dichloromethane-ethylacetate, 90:10) to give 0.189 g (72%) of the title material as longwhite plates. LC (Method A): 2.047 min. HRMS(ESI): Anal.Calcd forC₁₀H₂F₃N₂O₃S [M+H]⁺ m/z 297.0515; found 297.0526. ¹H NMR (CDCl₃, 400MHz) δ ppm: 3.94 (s, 3H), 3.78-3.87 (m, 4H), 3.50-3.59 (m, 4H).

86B. (2-Morpholino-5-(trifluoromethyl)thiazol-4-yl)methanol

A solution of methyl2-morpholino-5-(trifluoromethyl)thiazole-4-carboxylate (0.177 g, 0.597mmol) in tetrahydrofuran (4 mL) under nitrogen was cooled to 0° C. andtreated with methanol (0.048 mL, 1.19 mmol), followed by lithiumborohydride (0.026 g, 1.195 mmol) added all at once. After 30 min thecooling bath was removed and the resulting turbid solution was stirredat room temperature for 2.5 h. The reaction mixture was re-cooled inice, quenched with 50% aqueous acetic acid (two drops) and diluted withethyl acetate (100 mL). This mixture was washed with saturated sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The white solid residue obtainedwas chromatographed on silica gel (elution with ethyl acetate) to give0.144 g (90%) of the title material as a white solid. LC (Method A):1.833 min. HRMS(ESI): Anal.Calcd for C₉H₁₂F₃N₂O₂S [M+H]⁺ m/z 269.0566;found 269.0573. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.62 (d, J=5.9 Hz, 2H),3.82 (d, J=5.0 Hz, 4H), 3.51 (d, J=5.0 Hz, 4H), 2.57 (t, J=5.9 Hz, 1H).

Example 864-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)morpholine

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.080 g, 0.252 mmol) and2-morpholino-5-(trifluoromethyl)thiazol-4-yl)methanol (0.074 g, 0.277mmol) in dry tetrahydrofuran (10 mL) was treated at 22° C. and undernitrogen with tri-n-butylphosphine (0.128 g, 0.63 mmol) added in oneportion, followed by a solution of 1,1′-(azodicarbonyl)dipiperidine(0.102 g, 0.403 mmol) in tetrahydrofuran (2 mL) added dropwise over 30min. After another 2 h at 22° C., the reaction mixture was partitionedbetween dichloromethane and saturated sodium bicarbonate. The organicphase was washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo to give a glassy residue. Chromatography on silicagel (elution gradient of ethyl acetate in dichloromethane) gave 0.104 g(73%) of the title compound as a white solid, after trituration inacetonitrile. LC (Method A): 2.576 min. HRMS(ESI): Anal.Calcd forC₂₃H₂₁F₃N₅O₅S₂ [M+H]⁺ m/z 568.0931; found 568.0978. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.84 (s, 1H), 7.06 (s, 1H), 6.71 (br. s, 1H), 6.47 (d,J=1.6 Hz, 1H), 5.13 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.79-3.84 (m,4H), 3.48-3.55 (m, 4H).

Example 874-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-amine

87A. Methyl2-((tert-butoxycarbonyl)amino)-5-methylthiazole-4-carboxylate

A solution of methyl 2-amino-5-methylthiazole-4-carboxylate (1.00 g,5.81 mmol) in tetrahydrofuran (20 mL) was treated with di-tert-butyldicarbonate (1.27 g, 5.81 mmol), added all at once, followed bytriethylamine (1.619 mL, 11.61 mmol) and DMAP (0.040 g, 0.327 mmol). Theresulting solution was stirred at 22° C. for 18 h. The reaction mixturewas then diluted with ethyl acetate (200 mL) and water (50 mL) and theorganic phase was washed successively with water, cold 0.1 Nhydrochloric acid, saturated aqueous sodium bicarbonate, brine and driedover anhydrous magnesium sulfate. Evaporation of the solvent underreduced pressure gave a clear oil which was chromatographed on silicagel (elution with toluene-ethyl acetate, 8:2 to 7:3) to give 1.319 g(83%) of the title material as a pale yellow solid. LC (Method A): 2.049min. LCMS (APCI): Anal.Calcd for C₁₁H₁₅N₂O₄S [M−H]⁻ m/z 271; found 271.¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.24 (br. s., 1H), 3.90 (s, 3H), 2.69 (s,3H), 1.53 (s, 9H).

87B. Methyl2-((tert-butoxycarbonyl)(2,4-dimethoxybenzyl)amino)-5-methylthiazole-4-carboxylate,and (Z)-Methyl2-((tert-butoxycarbonyl)imino)-3-(2,4-dimethoxybenzyl)-5-methyl-2,3-dihydrothiazole-4-carboxylate

A mixture of methyl2-((tert-butoxycarbonyl)amino)-5-methylthiazole-4-carboxylate (1.18 g,4.33 mmol) and (2,4-dimethoxyphenyl)methanol (0.802 g, 4.77 mmol) in drytetrahydrofuran (40 mL) was treated at 22° C. with tri-n-butylphosphine(2.67 mL, 10.83 mmol), added all at once, followed by a solution of1,1′-(azodicarbonyl)dipiperidine (2.187 g, 8.67 mmol) in tetrahydrofuran(25 mL) added dropwise over 40 min. The mixture was stirred for another2 h and then it was partitioned between ethyl acetate (250 mL) andsaturated aqueous sodium bicarbonate (20 mL). The organic phase wasseparated, washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo to give a gel-like residue. Chromatography onsilica gel (elution with 0-5% ethyl acetate-toluene) gave 0.993 g (54%)of methyl2-((tert-butoxycarbonyl)(2,4-dimethoxybenzyl)amino)-5-methylthiazole-4-carboxylateas a white solid. LC (Method A): 2.388 min. HRMS(ESI): Anal.Calcd forC₂₀H₂₇N₂O₆S [M+H]⁺ m/z 423.1584; found 423.1474. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 6.96 (d, J=8.2 Hz, 1H), 6.43 (broad s, 1H), 6.38 (br d, J=8.2 Hz,1H), 5.28 (s, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 2.66 (s,3H), 1.43 (s, 9H). Further elution gave 0.287 g (16%) of (Z)-methyl2-((tert-butoxycarbonyl)imino)-3-(2,4-dimethoxybenzyl)-5-methyl-2,3-dihydrothiazole-4-carboxylateas a white solid. LC (Method A): 2.310 min. HRMS(ESI): Anal.Calcd forC₂₀H₂₇N₂O₆S [M+H]⁺ m/z 423.1584; found 423.1481. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 6.84 (d, J=8.2 Hz, 1H), 6.34-6.40 (m, 2H), 5.58 (s, 2H), 3.77 (s,3H), 3.76 (s, 3H), 3.73 (s, 3H), 2.42 (s, 3H), 1.55 (s, 9H).

87C. tert-Butyl2,4-dimethoxybenzyl(4-(hydroxymethyl)-5-methylthiazol-2-yl)carbamate

A solution of methyl2-((tert-butoxycarbonyl)(2,4-dimethoxybenzyl)amino)-5-methylthiazole-4-carboxylate(0.650 g, 1.538 mmol) in tetrahydrofuran (15 mL) and under nitrogen wascooled at 0° C. and treated with methanol (0.124 mL, 3.08 mmol),followed by lithium borohydride (0.134 g, 6.15 mmol), added all at once.After 10 min the cooling bath was removed and the resulting turbidsolution was stirred at room temperature for 6 h. The reaction mixturewas re-cooled in ice and quenched with 50% aqueous acetic acid (1 mL).After the evolution of hydrogen has ceased, the reaction mixture wasdiluted with dichloromethane (250 mL), washed with saturated sodiumbicarbonate and brine, and then dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the solid residue obtainedwas chromatographed on silica-gel (elution dichloromethane-ethyl acetate95:5 to 9:1) to give 0.488 g (80%) of the title material as a whitesolid. LC (Method A): 2.213 min. HRMS(ESI): Anal.Calcd for C₁₉H₂₇N₂O₅S[M+H]⁺ m/z 395.1635; found 395.1627. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 6.91(d, J=8.5 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 6.38 (dd, J=8.5, 2.1 Hz, 1H),5.23 (s, 2H), 4.49 (d, J=5.8 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 2.32(t, J=5.8 Hz, 1H), 2.29 (s, 3H), 1.46 (s, 9H).

87D. tert-Butyl2,4-dimethoxybenzyl(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)carbamate

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.378 g, 1.19 mmol) and tert-butyl2,4-dimethoxybenzyl(4-(hydroxymethyl)-5-methylthiazol-2-yl)carbamate(0.469 g, 1.19 mmol) in dry tetrahydrofuran (30 mL) was treated at 22°C. with tri-n-butylphosphine (0.88 mL, 3.57 mmol), added in one portion,followed by a solution of 1,1′-(azodicarbonyl)dipiperidine (0.450 g,1.785 mmol) in tetrahydrofuran (10 mL) added dropwise over 40 min. Afteranother 2 h at 22° C., the reaction mixture was partitioned betweendichloromethane (300 mL) and saturated aqueous sodium bicarbonate. Theorganic phase was washed with brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo to give a glassy residue.Chromatography on silica gel (elution with 0-5% ethylacetate-dichloromethane) gave 0.622 g (75%) of the title material as awhite solid. LC (Method A): 2.703 min. HRMS(ESI): Anal.Calcd forC₃₃H₃₆N₅O₈S₂ [M+H]⁺ m/z 694.2005; found 694.2006. ¹H NMR (CDCl₃, 400MHz) δ ppm: 7.83 (s, 1H), 7.01 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.67 (s,1H), 6.47 (br s, 1H), 6.43 (d, J=2.2 Hz, 1H), 6.37 (dd, J=8.5, 2.2 Hz,1H), 5.26 (s, 2H), 5.11 (s, 2H), 4.21 (s, 3H), 3.80 (s, 3H), 3.79 (s,3H), 3.78 (s, 3H), 2.41 (s, 3H), 1.44 (s, 9H).

Example 874-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-amine

To a mixture of tert-butyl2,4-dimethoxybenzyl(4-(((6-methoxy-2-(2-methoxyimidazo-[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)carbamate(0.643 g, 0.927 mmol) and 1,2,3,4,5-pentamethylbenzene (2.40 g, 16.19mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid(15 mL, 196 mmol) in one portion and the resulting clear solution wasstirred at 23° C. for 3 h. The volatiles were then evaporated underreduced pressure and the residue was partitioned between dichloromethane(500 mL) and saturated aqueous sodium bicarbonate. The aqueous phase wasseparated and back-extracted with dichloromethane (2×50 mL) and thecombined organic extract was washed with brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure to give a whiteresidue. This solid residue was chromatographed on silica gel (elutionwith 1-5% MeOH-dichloromethane) to give 0.351 g (85%) of the titlecompound as a white solid. LC (Method A): 2.189 min. HRMS(ESI):Anal.Calcd for C₁₉H₁₈N₅O₄S₂ [M+H]⁺ m/z 444.0795; found 444.0797. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 6.74(br s, 2H), 6.57 (d, J=1.6 Hz, 1H), 4.93 (s, 2H), 4.20 (s, 3H), 3.80 (s,3H), 2.26 (s, 3H).

Example 884-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-2-morpholinothiazole-5-carbaldehyde

88A. 4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)morpholine

A mixture of 2-bromo-4-((((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 2.46 g, 7.98 mmol) and morpholine (3.13 mL, 35.9 mmol) inTHF (7 mL) in a 50 mL pressure vial was heated at 83° C. for 48 h. Thecooled mixture was then evaporated under vacuum and the residue wasdiluted with ethyl acetate (200 mL) and washed successively with water,cold 0.1N HCl, saturated sodium bicarbonate and brine. After drying overanhydrous magnesium sulfate, the solvent was evaporated and the lightyellow oily residue obtained was purified by flash chromatography on theIsco (40 g cartridge, elution with 0-9% ethyl acetate-DCM) to give ayellow oil (1.98 g, 79%). Distillation (Kugelrohr) of this oil in vacuogave 1.85 g (74%) of the title compound as a light yellow oil: by105-115° C./0.04 torr. LC (Method F): 2.205 min. HRMS(ESI): calcd forC₁₄H₂₇N₂O₂SSi [M+H]⁺ m/z 315.156, found 315.158. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 6.47 (t, J=1.5 Hz, 1H), 4.67 (d, J=1.5 Hz, 2H), 3.74-3.90 (m,4H), 3.39-3.51 (m, 4H), 0.95 (s, 9H), 0.11 (s, 6H).

88B.4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-morpholinothiazole-5-carbaldehyde

A solution of4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)morpholine(0.400 g, 1.272 mmol) in anhydrous THF (10 mL) was cooled to −78° C.under nitrogen and then a solution of BuLi (1.6 M in hexanes, 1.11 ml,1.780 mmol) was added dropwise over 10 min. The resulting mixture wasstirred at −78° C. for 30 min and then dry DMF (0.591 mL, 7.63 mmol) wasadded dropwise. The mixture was stirred for 2 h at −78° C. and thenallowed to warm up to room temperature. After reaction completion (LC),saturated aqueous NH₄Cl (3 mL) was added and the resulting mixture wasstirred for 10 min at 20° C., then diluted in DCM (50 mL) and washedwith brine. The organic phase was dried (MgSO₄) and evaporated and theresidue was purified on the ISCO using a REDISEP® 12 g column (60 to100% DCM-hexanes) to give the title product as a bright yellow solid(0.20 g, 46%). LCMS (APCI): calcd for C₁₅H₂₇N₂O₃SSi [M+H]⁺ m/z 343.14,found 343.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 10.22 (s, 1H), 4.91 (s, 2H),3.78-3.83 (m, 4H), 3.56-3.63 (m, 4H), 0.94 (s, 9H), 0.14 (s, 6H).

88C. 4-(Hydroxymethyl)-2-morpholinothiazole-5-carbaldehyde

To a solution of4-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-morpholinothiazole-5-carbaldehyde(0.200 g, 0.584 mmol) in dry THF (5 mL) under N₂ was added TBAF (2.7 Min THF, 0.427 mL, 1.168 mmol) dropwise and the mixture was stirred atroom temperature for 2 h. The reaction mixture was then diluted with DCMand washed with aqueous NaHCO₃ and brine, and then it was dried overMgSO₄ and evaporated. The crude product was purified on the ISCO using aREDISEP® 4 g column (0 to 15% MeOH-DCM) to yield the product as a yellowsolid (0.102 g, 77%). LCMS (APCI): calcd for C₉H₁₃N₂O₃S [M+H]⁺ m/z229.06, found 229.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 9.88 (s, 1H), 4.84(d, J=5.9 Hz, 2H), 3.78-3.87 (m, 4H), 3.59-3.68 (m, 4H), 2.77 (t, J=5.1Hz, 1H).

Example 884-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-2-morpholinothiazole-5-carbaldehyde

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.139 g, 0.438 mmol) and4-(hydroxymethyl)-2-morpholinothiazole-5-carbaldehyde (0.100 g, 0.438mmol) were reacted as described in Example 86. The reaction mixture wasconcentrated in vacuo and the crude residue was suspended in CH₃CN,sonicated and filtered. The resulting solid was purified on the ISCOusing a REDISEP® Gold 4 g column (0 to 60% EtOAc-DCM). The obtainedmaterial was suspended in CH₃CN, sonicated, filtered and dried to givethe title compound as an off-white solid (0.100 g, 43%). LC (Method C):2.287 min. HRMS(ESI): calcd for C₂₃H₂₂N₅O₆S₂ [M+H]⁺ m/z 528.093, found528.0988. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 10.15 (s, 1H), 7.85 (s, 1H),7.03 (s, 1H), 6.74 (s, 1H), 6.45 (d, J=1.6 Hz, 1H), 5.36 (s, 2H), 4.22(s, 3H), 3.85 (s, 3H), 3.81-3.85 (m, 4H), 3.65 (t, J=4.7 Hz, 4H).

Example 89(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-2-morpholinothiazol-5-yl)methanol

A solution of4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-2-morpholinothiazole-5-carbaldehyde(0.088 g, 0.167 mmol) in dry THF (10 mL) in a 50 mL flask under anitrogen atmosphere was cooled to 0° C. and treated with MeOH (6.75 μl,0.167 mmol) followed by LiBH₄ (3.63 mg, 0.167 mmol). The resultingmixture was stirred at 0° C. for 1 h before to be quenched with MeOH (5mL) and stirred at room temperature for 10 min. Then the reactionmixture was diluted with DCM, washed with aqueous NaHCO₃ and brine,dried over MgSO₄ and evaporated. The residue was purified on the ISCOusing a REDISEP® 4 g column (0 to 100% EtOAc-DCM) to give the titlecompound as a white solid (0.084 g, 95%). LC (Method C): 2.062 min.HRMS(ESI): calcd for C₂₃H₂₄N₅O₆S₂ [M+H]⁺ m/z 530.109, found 530.114. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 7.84 (s, 1H), 7.04 (d, J=0.8 Hz, 1H), 6.72(d, J=0.8 Hz, 1H), 6.48-6.53 (m, 1H), 5.11-5.17 (m, 2H), 4.77-4.83 (m,2H), 4.26 (s, 1H), 4.21 (s, 2H), 3.79-3.87 (m, 7H), 3.45-3.52 (m, 4H),1.91 (t, J=6.3 Hz, 1H).

Example 904-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-(methoxymethyl)thiazol-2-yl)morpholine

90A. Ethyl4-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-morpholinothiazole-5-carboxylate

A solution of4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)morpholine(Example 88A, 0.060 g, 0.191 mmol) in dry THF (2 mL) was cooled at −78°C. under N₂ and then n-butyllithium (1.5 M in hexanes, 0.165 mL, 0.248mmol) was added dropwise. The resulting pale yellow solution was stirredfor 35 min at the same temperature and then ethyl chloroformate (0.027mL, 0.286 mmol) was added dropwise. The resulting mixture was allowed towarm to room temperature over 2 h and then it was partitioned betweenethyl acetate and saturated aqueous ammonium chloride. The organic phasewas separated, washed with brine, dried over anhydrous magnesium sulfateand evaporated in vacuo. Chromatography of the residue on silica gel(ISCO, elution gradient of ethyl acetate in dichloromethane) gave 0.065g (88%) of the title compound. LC (Method B): 2.999 min. LCMS (APCI):calcd for C₁₇H₃₁N₂O₄SSi [M+H]⁺ m/z 387.18; found 387.2.

90B.(4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-morpholinothiazol-5-yl)methanol

To an ice-cold solution of ethyl4-(((tert-butyldimethylsilyl)oxy)methyl)-2-morpholinothiazole-5-carboxylate(0.065 g, 0.168 mmol) in tetrahydrofuran (5 mL) was added methanol(0.020 mL, 0.504 mmol), followed by lithium borohydride (0.0073 g, 0.336mmol). After 15 min at 0° C., the cooling bath was removed and thereaction mixture was allowed to warm to ambient temperature while beingstirred for 3 h. The reaction mixture was then partitioned withdichloromethane-saturated aqueous ammonium chloride and the aqueousphase was separated and back-extracted with dichloromethane (×3). Thecombined organic extract was washed with brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. Chromatography of the residueon silica gel (ISCO, elution gradient of ethyl acetate indichloromethane) gave 0.048 g (83%) of the title compound. LC (MethodA): 2.017 min. HRMS(ESI): calcd for C₁₅H₂₉N₂O₃SSi [M+H]⁺ m/z 345.1668;found 345.1662. ¹H NMR (400 MHz, CDCl₃) δ ppm: 4.74 (s, 2H), 4.68 (d,J=6.2 Hz, 2H), 3.74-3.84 (m, 4H), 3.36-3.47 (m, 4H), 2.63 (t, J=6.2 Hz,1H), 0.94 (s, 9H, 0.15 (s, 6H).

90C.4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(methoxymethyl)thiazol-2-yl)morpholine

To a solution of(4-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-morpholinothiazol-5-yl)methanol(0.048 g, 0.139 mmol) in N,N-dimethylformamide (2.5 mL), cooled at −15°C. under nitrogen, was added sodium hydride (60% dispersion in oil,0.017 g, 0.418 mmol) and the mixture was stirred at −15° C. to −10° C.for 25 min. Iodomethane (0.044 mL, 0.697 mmol) was then added and theresulting mixture was stirred at the same temperature for 4 h, beforebeing partitioned between ether and saturated aqueous ammonium chloride.The aqueous phase was separated and back-extracted with ether (×3), andthe combined organic extract was washed with brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. This gave the title compound(0.050 g, 100%) which was used as such in the next step without furtherpurification. LC (Method A): 2.224 min. HRMS(ESI): calcd forC₁₋₆H₃₁N₂O₃SSi [M+H]⁺ m/z 359.1825; found 359.1819.

90D. (5-(Methoxymethyl)-2-morpholinothiazol-4-yl)methanol

A solution of4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(methoxymethyl)thiazol-2-yl)morpholine(0.050 g, 0.139 mmol) in dry tetrahydrofuran (4 mL) under nitrogen wastreated dropwise with triethylamine trihydrofluoride (0.136 mL, 0.837mmol) and the resulting mixture was stirred at room temperature for 36h. The reaction mixture was then partitioned withdichloromethane-saturated aqueous sodium bicarbonate and the organicphase was separated, washed with brine, dried over anhydrous magnesiumsulfate and evaporated in vacuo. Chromatography of the residue on silicagel (ISCO, elution gradient of ethyl acetate in dichloromethane) gave0.025 g (74%) of the title compound as a white crystalline solid. LC(Method A): 0.933 min. HRMS(ESI): calcd for C₁₀H₁₇N₂O₃S [M+H]⁺ m/z245.0960; found 245.0954. ¹H NMR (400 MHz, CDCl₃) δ ppm: 4.55 (s, 2H),4.49 (s, 2H), 3.77-3.84 (m, 4H), 3.41-3.49 (m, 4H), 3.35 (s, 3H), 2.46(br s, 1H).

Example 904-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-(methoxymethyl)thiazol-2-yl)morpholine

The title compound was prepared according to the general Mitsunobucoupling procedure described in Example 86. LC (Method A): 2.191 min.HRMS(ESI): calcd for C₂₄H₂₆N₅O₆S₂[M+H]⁺ m/z 544.1325; found 544.1322. ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.83 (s, 1H), 7.03 (s, 1H), 6.70 (d, J=0.78Hz, 1H), 6.47-6.52 (m, 1H), 5.10 (s, 2H), 4.60 (s, 2H), 4.20 (s, 3H),3.77-3.89 (m, 7H), 3.43-3.52 (m, 4H), 3.33 (s, 3H).

Example 912-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-2-morpholinothiazol-5-yl)propan-2-ol

91A.2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-morpholinothiazol-5-yl)propan-2-ol

A solution of4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)morpholine(Example 88A, 0.100 g, 0.318 mmol) in dry THF (5 mL) was cooled at −78°C. under nitrogen and then a solution of n-BuLi (1.26 M in hexanes,0.454 mL, 0.572 mmol) was added dropwise over 10 min. The resultingmixture was stirred at −78° C. for 30 min and then dry acetone (1.0 mL,13.62 mmol) was added dropwise. The reaction mixture was allowed to warmto room temperature and was stirred for another 2 h before beingquenched with saturated aqueous NH₄Cl (5 mL). The mixture was dilutedwith DCM (50 mL), washed with brine and, after concentration underreduced pressure, the crude material was purified on the ISCO using aREDISEP® 4 g column (0 to 50% EtOAc-DCM) to give the desired product(0.040 g, 25%) as a colorless oil which was used as such in the nextstep. LC (Method A): 2.072 min. LCMS (APCI): calcd for C₁₇H₃₃N₂O₃SSi[M+H]⁺ m/z 373.20, found 373.20.

91B. 2-(4-(Hydroxymethyl)-2-morpholinothiazol-5-yl)propan-2-ol

To a solution of2-(4-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-morpholinothiazol-5-yl)propan-2-ol(0.040 g, 0.107 mmol) in dry THF (2 mL) under N₂ was added triethylaminetrihydrofluoride (0.105 mL, 0.644 mmol) dropwise and the mixture wasstirred at room temperature overnight. The reaction mixture was thendiluted with DCM and the solution was washed with aqueous NaHCO₃, driedover MgSO₄ and evaporated. The residue was purified on the ISCO using aREDISEP® 4 g column (0 to 15% MeOH-DCM) to give the title compound as awhite solid (0.019 g, 69%). LCMS (APCI): calcd for C₁₁H₁₉N₂O₃S [M+H]⁺m/z 259.104, found 259.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.70 (s, 2H),3.76-3.83 (m, 4H), 3.36-3.43 (m, 4H), 3.07 (br. s., 1H), 2.94 (br. s.,1H), 1.63 (s, 6H).

Example 912-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-2-morpholinothiazol-5-yl)propan-2-ol

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.023 g, 0.074 mmol) and2-(4-(hydroxymethyl)-2-morpholinothiazol-5-yl) propan-2-ol (0.019 g,0.074 mmol) were reacted as described in Example 86. The reactionmixture was concentrated in vacuo and the residue was suspended inCH₃CN, sonicated and filtered. The resulting solid was purified on theISCO using a REDISEP® Gold 4 g column (0 to 70% EtOAc-DCM) and theobtained material was suspended in CH₃CN, sonicated, filtered and driedto give the title compound as an off-white solid (0.005 g, 13%). LC(Method C): 2.047 min. HRMS(ESI): calcd for C₂₅H₂₈N₅O₆S₂ [M+H]⁺ m/z558.140, found 558.1482. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.84 (s, 1H),7.03 (s, 1H), 6.68-6.72 (m, 1H), 6.57 (d, J=2.0 Hz, 1H), 5.24 (s, 2H),4.21 (s, 3H), 3.85 (s, 3H), 3.78-3.84 (m, 4H), 3.41-3.47 (m, 4H), 2.89(s, 1H), 1.64 (s, 6H).

Example 923-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

92A. Methyl2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)thiazole-4-carboxylate

A solution of bicyclomorpholine (0.52 mL, 4.75 mmol) in THF (10 mL) wastreated with methyl 2-bromothiazole-4-carboxylate (1.0 g, 4.24 mmol) andDIEA (1.66 mL, 9.50 mmol) and the resulting mixture was refluxed for 18h under N₂. The reaction mixture was then concentrated under reducedpressure and the residue was purified on the ISCO using a REDISEP® 24 gcolumn (0 to 40% EtOAc-DCM) to give the desired product as a yellow gum(0.740 g, 62%). LCMS (APCI): calcd for C₁₁H₁₅N₂O₃S [M+H]⁺ m/z 255.07,found 255.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.48 (s, 1H), 4.48 (d, J=2.7Hz, 2H), 3.89 (s, 3H), 3.58 (d, J=12.1 Hz, 2H), 3.37 (dd, J=11.9, 2.5Hz, 2H), 1.98-2.07 (m, 2H), 1.86-1.94 (m, 2H).

92B. (2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)thiazole-4-yl)methanol

A solution of methyl2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)thiazole-4-carboxylate (0.740 g,2.91 mmol) in dry THF (15 mL) in a 50 mL flask under a nitrogenatmosphere was cooled to 0° C. and treated with LiBH₄ (0.127 g, 5.82mmol) followed by MeOH (0.24 mL, 5.82 mmol). After 10 min at 0° C. thebath was removed and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was then quenched with MeOH(10 mL), concentrated under reduced pressure and the residue wasdissolved in DCM and dried over MgSO₄. The volatiles were removed underreduced pressure and the residue was purified on the ISCO using aREDISEP® 24 g column (0 to 15% MeOH-DCM) to give the title alcohol (0.60g, 91%) as a colorless oil which solidified on standing in vacuo to givea white solid. LCMS (APCI): calcd for C₁₀H₁₅N₂O₂S [M+H]⁺ m/z 227.08,found 227.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 6.41 (s, 1H), 4.53 (s, 2H),4.02 (dt, J=12.2, 6.2 Hz, 2H), 3.49 (d, J=11.7 Hz, 2H), 3.30 (dd,J=12.1, 2.0 Hz, 2H), 2.78 (br.s., 1H), 1.96-2.03 (m, 2H), 1.88-1.92 (m,2H).

Example 923-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.070 g, 0.22 mmol) and(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)thiazol-4-yl)methanol (0.055 g,0.24 mmol) were reacted as described in Example 86. The crude materialwas purified on the ISCO using a REDISEP® Gold 4 g column (0 to 45%EtOAc-DCM) and the obtained material was triturated with CH₃CN to givethe title compound as a cream solid (0.032 g, 28%). LC (Method C): 2.262min. HRMS(ESI): calcd for C₂₄H₂₄N₅O₅S₂ [M+H]⁺ m/z 526.114, found526.124. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.37 (s, 1H), 6.98 (s, 1H), 6.92(s, 1H), 6.82 (s, 1H), 6.56 (d, J=2.0 Hz, 1H), 4.42 (br. s., 2H), 4.20(s, 3H), 3.80 (s, 3H), 3.47 (d, J=11.7 Hz, 3H), 3.14-3.19 (m, 3H), 1.86(d, J=8.2 Hz, 2H), 1.76-1.80 (m, 2H).

Example 933-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-8-oxa-3-azabicyclo-[3.2.1]-octane

93A.3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

To a solution of(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)thiazol-4-yl)methanol (0.490 g,2.165 mmol) in DMF (10 mL) cooled at 0° C. under N₂, was added TBDMS-Cl(0.653 g, 4.33 mmol) and then imidazole (0.339 g, 4.98 mmol). Thereaction mixture was brought to room temperature over 10 min and wasstirred at the same temperature for 18 h. The mixture was then re-cooledat 0° C. and EtOH (2 mL) was added. After 10 min the mixture was allowedto warm to room temperature and was then partitioned between EtOAc andsaturated aqueous NaHCO₃. The organic layer was washed with brine, driedover MgSO₄, filtered and evaporated. The residue was purified on theISCO using a REDISEP® 12 g column (0 to 20% EtOAc-DCM) to give thedesired product as a colorless oil (0.70 g, 95%). LCMS (APCI): calcd forC₁₆H₂₉N₂O₂SSi [M+H]⁺ m/z 341.16, found 341.2. ¹H NMR (CDCl₃, 400 MHz) δppm: 6.30 (s, 1H), 4.55 (s, 2H), 4.32-4.37 (m, 2H), 3.38 (d, J=11.7 Hz,2H), 3.18 (dd, J=11.7, 2.3 Hz, 2H), 1.84-1.91 (m, 2H), 1.76-1.83 (m,2H), 0.83 (s, 9H), 0.00 (s, 6H).

93B.3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

A solution of3-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane(0.700 g, 2.055 mmol) in anhydrous THF (20 mL) was cooled at −78° C.under nitrogen and a solution of BuLi (1.6 M in hexanes, 2.70 mL, 4.32mmol) was added dropwise over 10 min. The resulting mixture was stirredat −78° C. for 30 min and then it was treated dropwise with iodomethane(0.257 mL, 4.11 mmol). The cooling bath was removed and the mixture wasstirred for 2 h at room temperature before being quenched with saturatedaqueous NH₄Cl (5 mL). After stirring for 10 min, the mixture was dilutedwith DCM (100 mL) and washed with brine. The organic phase was dried(MgSO₄) and evaporated and the residue was purified on the ISCO using aREDISEP® 24 g column (0 to 40% EtOAc-DCM) to give the desired product asa yellow oil (0.514 g, 71%). LCMS (APCI): calcd for C₁₇H_(3i)N₂O₂SSi[M+H]⁺ m/z 355.18, found 355.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.55-4.61(m, 2H), 4.40-4.47 (m, 2H), 3.44 (d, J=12.1 Hz, 2H), 3.24 (dd, J=12.1,2.3 Hz, 2H), 2.31 (s, 3H), 1.93-2.01 (m, 2H), 1.85-1.93 (m, 2H), 0.92(s, 9H), 0.10 (s, 6H).

93C.(2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methylthiazol-4-yl)methanol

To a solution of3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane(0.514 g, 1.450 mmol) in dry THF (10 mL) under N₂ was addedtriethylamine trihydrofluoride (1.3 mL, 7.98 mmol) dropwise and themixture was stirred at room temperature overnight. The reaction mixturewas then quenched with MeOH and concentrated under reduced pressure. Theresidue was purified on the ISCO using a REDISEP® 12 g column (0 to 15%MeOH-DCM) to give the title product as an off-white solid (0.278 g,80%). LCMS (APCI): calcd for C₁₁H₁₇N₂O₂S [M+H]⁺ m/z 241.09, found 241.1.¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.35-4.41 (m, 4H), 3.62 (t, J=5.7 Hz,1H), 3.45 (d, J=12.1 Hz, 2H), 3.10 (dd, J=12.1, 2.3 Hz, 2H), 2.26 (s,3H), 1.86-1.94 (m, 2H), 1.79-1.86 (m, 2H).

Example 933-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-8-oxa-3-azabicyclo-[3.2.1]-octane

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.070 g, 0.22 mmol) and(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methylthiazol-4-yl)methanol(0.058 g, 0.24 mmol) were reacted as described in Example 86. Thereaction mixture was concentrated under vacuum and the residue wassuspended in CH₃CN, sonicated and filtered. The resulting solid waspurified on the ISCO using a REDISEP® Gold 4 g column (0 to 70%EtOAc-DCM) to give the title compound as a white solid (0.056 g, 47%).LC (Method C): 2.182 min. LCMS (APCI): calcd for C₂₅H₂₆N₅O₅S₂ [M+H]⁺ m/z540.130, found 540.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.33 (s, 1H), 6.87(s, 1H), 6.78 (s, 1H), 6.57 (d, J=1.6 Hz, 1H), 4.96 (s, 2H), 4.37 (br.s., 2H), 4.17 (s, 3H), 3.77 (s, 3H), 3.37 (d, J=11.7 Hz, 2H), 3.08 (dd,J=11.8, 2.2 Hz, 2H), 2.28 (s, 3H), 1.78-1.87 (m, 2H), 1.68-1.78 (m, 2H).

Example 944-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)morpholine

94A. Methyl 5-methyl-2-morpholinothiazole-4-carboxylate

A solution of methyl 2-bromo-5-methylthiazole-4-carboxylate (2.80 g,11.86 mmol) and morpholine (4.5 mL, 51.7 mmol) in THF (10 mL) was heatedat reflux under nitrogen for 18 h. The volatiles were then removed underreduced pressure and the crude product was purified on the ISCO using aREDISEP® 40 g column (0 to 40% EtOAc-DCM), to give the title compound(2.20 g, 77%) as a yellow solid. LCMS (APCI): calcd for C₁₀H₁₅N₂O₃S[M+H]⁺ m/z 243.07, found 243.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 3.89 (s,3H), 3.77-3.83 (m, 4H), 3.41-3.47 (m, 4H), 2.64 (s, 3H).

Alternatively, Example 94A, methyl5-methyl-2-morpholinothiazole-4-carboxylate, was prepared as follows:

94AA. Methyl 3-bromo-2-oxobutanoate

A 5 L 4-neck round bottom flask equipped with a mechanical stirrer,temperature thermocouple, condenser and a 1 L addition funnel, wascharged copper(II) bromide (962 g, 4310 mmol) and ethyl acetate (2 L). Asolution of methyl 2-ketobutyrate (250 g, 2150 mmol) in CHCl₃ (828 mL)was added dropwise. A scrubber (400 mL 1 N NaOH) was connected and thereaction mixture was heated to reflux (75° C.). The reaction started asa dark green color and as heating progressed, it became a light greenwith a white precipitate forming. NMR after one hour at reflux indicatedthat the reaction was complete. The reaction was cooled to RT andfiltered through a pad of CELITE®. The filtrate was concentrated to anoil, dissolved in methylene chloride (500 mL) and filtered again throughCELITE®. The filtrate was then passed through a pad of silica gel andeluted with ethyl acetate. Concentration of the filtrate provided thetitle bromoketoester (399 g, 2040 mmol, 95%) as a yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 5.18 (q, J=6.7 Hz, 1H), 3.94 (s, 3H), 1.83 (d, J=6.8Hz, 3H).

94AAA. Morpholine-4-carbothioamide

To a solution of morpholine (199 g, 2280 mmol) in CHCl₃ (1 L) was addedisothiocyanatotrimethylsilane (150 g, 1140 mmol) dropwise. A whiteprecipitate formed almost immediately, and the reaction was stirred for1 h at RT. The reaction was then filtered and the resulting solid waswashed with additional CHCl₃ and dried in vacuo to give the titlethiourea as a white solid. (137 g, 937 mmol, 82%). ¹H NMR (400 MHz,DMSO-d₆) δ 3.81-3.71 (m, 2H), 3.17-3.08 (m, 2H).

94A. Methyl 5-methyl-2-morpholinothiazole-4-carboxylate

To a solution of morpholine-4-carbothioamide (Example 94AAA, 175 g, 1200mmol) in methanol (500 mL) was charged methyl 3-bromo-2-oxobutanoate(Example 94AA, 233 g, 1200 mmol). The reaction was then heated to refluxfor 1 hour, cooled to RT, and filtered. The filtrate was concentratedand the crude product was purified on by silica gel chromatography. Thetitle thiazole (206 g, 850 mmol, 71%) was isolated as a yellow oil. (Seethe procedure set forth above for analytical data).

94B. (5-Methyl-2-morpholinothiazol-4-yl)methanol

The compound was prepared according to the protocol described forExample 92B. The crude product was purified on the ISCO using a REDISEP®Gold 24 g column (0 to 50% EtOAc-DCM) to give the title compound as awhite solid (0.086 g, 51%). LCMS (APCI): calcd for C₉H₁₅N₂O₂S [M+H]⁺ m/z215.08, found 215.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.48 (d, J=4.7 Hz,2H), 3.77-3.83 (m, 4H), 3.37-3.43 (m, 4H), 2.30 (t, J=4.7 Hz, 1H), 2.28(s, 3H).

Example 944-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)morpholine

The title compound was prepared according to the protocol described forExample 86. The crude product was purified on the ISCO using a REDISEP®4 g column (0 to 40% EtOAc-DCM) and the obtained solid was suspended inMeOH, sonicated, filtered and dried to give the title compound as anoff-white solid (0.094 g, 53%). LC (Method C): 2.314 min. HRMS(ESI):calcd for C₂₃H₂₄N₅O₅S₂ [M+H]⁺ m/z 514.122, found 514.126. ¹H NMR (CDCl₃,400 MHz) δ ppm: 7.83 (s, 1H), 7.06 (d, J=0.8 Hz, 1H), 6.69 (d, J=0.8 Hz,1H), 6.50 (d, J=2.0 Hz, 1H), 5.05 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H),3.78-3.84 (m, 4H), 3.39-3.46 (m, 4H), 2.37 (s, 3H).

Example 952-Methoxy-6-(6-methoxy-4-((5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

95A.4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(tetrahydro-2H-pyran-4-yl)thiazole

To a solution of (2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol(0.075 g, 0.376 mmol) in dichloromethane (5 mL) at room temperature wasadded imidazole (0.0384 g, 0.565 mmol), followed bytert-butylchlorodimethylsilane (0.071 g, 0.470 mmol). The resultingreaction mixture was stirred at room temperature for 18 h and then itwas quenched with methanol and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (Isco, 24 gcartridge) eluting with a gradient of ethyl acetate in dichloromethane(from 0 to 50%) to give the pure title compound (0.102 g, 86%). LC(Method A): 2.416 min. LCMS (APCI) calcd for C₁₅H₂₈NO₂SSi [M+H]⁺ m/z314.16, found 314.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 0.11 (s, 6H), 0.94(s, 9H), 1.82-1.94 (m, 2H), 1.99-2.07 (m, 2H), 3.16-3.26 (m, 1H), 3.53(td, J=2.5, 11.7 Hz, 2H), 4.02-4.09 (m, 2H), 4.84 (s, 2H), 7.06 (s, 1H).

95B. (5-Methyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

To a solution of4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(tetrahydro-2H-pyran-4-yl)thiazole(1.38 g, 4.40 mmol) in dry THF (50 mL), at −78° C. under nitrogen, wasadded n-BuLi (1.5 M in hexanes, 4.40 mL, 6.60 mmol) dropwise. Thereaction mixture was stirred for 20 min at the same temperature beforemethyl iodide (0.826 mL, 13.20 mmol) was added. The resulting reactionmixture was then warmed to −20° C. over 2 h and then it was quenchedwith methanol and concentrated under reduced pressure. The crude residueobtained was dissolved in dichloromethane, washed with water and brine,dried (MgSO₄) and evaporated. The crude product (1.44 g, 100%) was usedas such for the next step. LC (Method A): 2.648 min. LCMS (APCI): calcdfor C₁₆H₃₀NO₂SSi [M+H]⁺ m/z 328.18, found 328.2.

To a solution of4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazole(1.44 g, 4.40 mmol) in THF (30 mL) at room temperature was added TBAF(75% solution in water, 2.381 mL, 6.60 mmol) and the resulting mixturewas stirred at room temperature for 2 h. Another equivalent of TBAF (75%solution in water, 1.587 mL, 4.40 mmol) was then added and stirring wascontinued for another 3 h at room temperature. The reaction mixture wasquenched with water and the product was extracted with dichloromethane(3×). The combined organic extracts were washed with brine, dried overMgSO₄, filtered and concentrated. The crude residue obtained waspurified by column chromatography (Isco, 40 g cartridge) eluting with agradient of ethyl acetate in dichloromethane (0 to 100%) to give thetitle compound as a white solid (0.782 g, 83%). LC (Method A): 1.255min. LCMS (APCI): calcd for C₁₀H₁₆NO₂S [M+H]⁺ m/z 214.09, found 214.2.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.59-1.72 (m, 2H), 1.85-1.94 (m, 2H),2.38 (s, 3H), 3.08-3.20 (m, 1H), 3.43 (td, J=1.6, 11.3 Hz, 2H),3.87-3.93 (m, 2H), 4.42 (s, 2H), 4.98 (br s, 1H).

95C. 4-(Bromomethyl)-5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazole

To a solution of(5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (250 mg,1.172 mmol) in dichloromethane (25 mL) cooled at 0° C.,tribromophosphine (0.055 mL, 0.586 mmol) was added. After 5 minstirring, the cooling bath was removed and the solution was stirred atroom temperature for 3 h. The reaction mixture was poured into a mixtureof ethyl acetate and saturated aqueous sodium bicarbonate and theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude residue obtained was purified by columnchromatography (Isco, 12 g cartridge) eluting with a mixture of ethylacetate in dichloromethane (1:1) to give the product as a white solid(0.285 g, 88%). LC (Method A): 1.828 min. LCMS (APCI): calcd forC₁₀H₁₅BrNOS [M+H]⁺ m/z 276.01, found 276.0. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 1.58-1.72 (m, 2H), 1.87-1.96 (m, 2H), 2.39 (s, 3H), 3.10-3.22 (m,1H), 3.43 (td, J=2.0, 11.3 Hz, 2H), 3.87-3.94 (m, 2H), 4.70 (s, 2H).

Example 952-Methoxy-6-(6-methoxy-4-((5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a solution of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.060 g, 0.189 mmol) and4-(bromomethyl)-5-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazole (0.055 g,0.199 mmol) in DMF (5 mL) under nitrogen was added potassium carbonate(0.065 g, 0.473 mmol) and the resulting mixture was stirred at roomtemperature for 1.25 h. The crude reaction mixture was dissolved withdichloromethane, washed with water and brine, dried over MgSO₄, filteredand concentrated. The crude residue obtained was purified by columnchromatography (Isco, 12 g cartridge) eluting with a gradient of ethylacetate in dichloromethane (from 0 to 50%). The white solid obtained wastriturated in acetonitrile to give the title compound as a white solid(0.050 g, 52%). LC (Method A): 2.348 min. LCMS (ESI): calcd forC₂₄H₂₅N₄O₅S₂ [M+H]⁺ m/z 513.1266, found 513.1299. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 1.62-1.75 (m, 2H), 1.91-1.98 (m, 2H), 2.46 (s, 3H),3.15-3.25 (m, 1H), 3.45 (td, J=1.6, 11.3 Hz, 2H), 3.81 (s, 3H),3.87-3.94 (m, 2H), 4.20 (s, 3H), 5.19 (s, 2H), 6.64 (s, 1H), 6.83 (s,1H), 6.89 (s, 1H), 8.37 (s, 1H).

Example 964-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)oxazol-2-yl)morpholine

96A. Ethyl 2-morpholinooxazole-4-carboxylate

To a solution of morpholine (1.5 mL, 17.22 mmol) in dry THF (10 mL) wasadded ethyl 2-bromooxazole-4-carboxylate (1.00 g, 4.55 mmol). Then themixture was heated at 95° C. for 18 h under N₂. The reaction mixture wasconcentrated under reduced pressure and the crude material was purifiedon the ISCO using a REDISEP® 24 g column (0 to 60% EtOAc-DCM) to givethe title compound as a yellow oil (1.02 g, 99%). LCMS (APCI): calcd forC₁₀H₁₅N₂O₄ [M+H]⁺ m/z 227.10, found 227.1. ¹H NMR (CDCl₃, 400 MHz) δppm: 7.80 (s, 1H), 4.36 (q, J=7.0 Hz, 2H), 3.73-3.81 (m, 4H), 3.51-3.59(m, 4H), 1.36 (t, J=7.1 Hz, 3H).

96B. (2-Morpholinooxazol-4-yl)methanol

The compound was prepared from ethyl 2-morpholinooxazole-4-carboxylate(1.029 g, 4.55 mmol) by using the protocol described in Example 92B. Thecrude product mixture was purified on the ISCO using a REDISEP® Gold 12g column (0 to 15% MeOH-DCM) to give the title compound as a white solid(0.354 g, 42%). LCMS (APCI): calcd for C₈H₁₃N₂O₃ [M+H]⁺ m/z 185.09,found 185.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.18 (s, 1H), 4.48 (d, J=5.7Hz, 2H), 3.73-3.82 (m, 4H), 3.44-3.54 (m, 4H), 2.65 (t, J=5.7 Hz, 1H).

Example 964-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)oxazol-2-yl)morpholine

The title compound was prepared according to the general proceduredescribed for Example 86. The crude product was purified on the ISCOusing a REDISEP® Gold 4 g column (0 to 80% EtOAc-DCM) and the obtainedmaterial was suspended in CH₃CN, sonicated, filtered and dried to givethe title compound as a white solid (0.060 g, 56%). LC (Method C): 2.173min. HRMS(ESI): calcd for C₂₂H₂₂N₅O₆S [M+H]⁺ m/z 483.129, found 484.132.¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.84 (s, 1H), 7.29 (s, 1H), 7.07 (s, 1H),6.70 (s, 1H), 6.43 (d, J=1.6 Hz, 1H), 5.02 (s, 2H), 4.21 (s, 3H), 3.85(s, 3H), 3.77-3.82 (m, 4H), 3.50-3.55 (m, 4H).

Example 974-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methyloxazol-2-yl)morpholine

97A. 4-(4(((tert-Butyldimethylsilyl)oxy)methyl)oxazol-2-yl)morpholine

The title compound was prepared from (2-morpholinooxazol-4-yl)methanol(0.250 g, 1.36 mmol) by using the protocol described for Example 92C.The crude product mixture was purified on the ISCO using a REDISEP® Gold12 g column (0 to 15% MeOH-DCM) to give the title compound as a whitesolid (0.354 g, 42%). LCMS (APCI): calcd for C₁₄H₂₇N₂O₃Si [M+H]⁺ m/z299.17, found 299.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.11 (t, J=1.4 Hz,1H), 4.57 (d, J=1.6 Hz, 2H), 3.74-3.81 (m, 4H), 3.44-3.50 (m, 4H),0.91-0.95 (m, 9H), 0.12 (s, 6H).

97B.4-(4-(((tert-Butyl(ethyl)(methyl)silyl)oxy)methyl)-5-methyloxazol-2-yl)morpholine

The title compound was prepared from4-(4(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)morpholine (0.296g, 0.99 mmol) according to the protocol described in Example 93B. Thecrude product mixture was purified on the ISCO using a REDISEP® Gold 12g column (0 to 60% EtOAc-DCM) to give the title compound as a colorlessoil (0.127 g, 32%). LCMS (APCI): calcd for C₁₆H₃₁N₂O₃Si [M+H]⁺ m/z327.20, found 327.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.53 (s, 2H),3.73-3.80 (m, 4H), 3.39-3.46 (m, 4H), 2.24 (d, J=0.8 Hz, 3H), 0.97-1.04(m, 3H), 0.91-0.96 (m, 9H), 0.73 (s, 1H), 0.60 (s, 1H), 0.11 (s, 3H).

97C. (5-Methyl-2-morpholinooxazol-4-yl)methanol

The title compound was prepared from4-(4(((tert-butyl(ethyl)(methyl)silyl)oxy)methyl)-5-methyloxazol-2-yl)morpholine(0.124 g, 0.38 mmol) according to the protocol described in Example 93C.The crude product mixture was purified on the ISCO using a REDISEP® Gold4 g column (0 to 15% MeOH-DCM) to give an oil which was dissolved in DCM(100 mL) and washed with 1N HCl (2×30 mL). The aqueous layer wasbasified with solid Na₂CO₃ to pH 8 and then it was back-extracted withDCM (5×20 mL). The combined organic phase was dried over MgSO₄, filteredand concentrated to give the desired product as the free base (0.035 g,34%). LCMS (APCI): calcd for C₉H₁₅N₂O₃ [M+H]⁺ m/z 199.11, found 199.1.¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.42 (br s, 2H), 3.74-3.81 (m, 4H),3.41-3.48 (m, 4H), 2.18-2.26 (m, 4H).

Example 974-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methyloxazol-2-yl)morpholine

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.042 g, 0.13 mmol) and(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methylthiazol-4-yl)methanol(0.026 g, 0.13 mmol) were reacted as described in Example 86. Thereaction mixture was concentrated in vacuo and the residue was suspendedin CH₃CN, sonicated and filtered. The resulting solid was purified onthe ISCO using a REDISEP® Gold 4 g column (0 to 70% EtOAc-DCM) and theobtained material was suspended in CH₃CN, sonicated, filtered and driedto give the title compound as an off-white solid (0.022 g, 34%). LC(Method C): 2.126 min. LCMS (APCI): calcd for C₂₃H₂₄N₅O₆S [M+H]⁺ m/z498.14, found 498.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.84 (s, 1H), 7.05(s, 1H), 6.70 (s, 1H), 6.45 (d, J=2.0 Hz, 1H), 4.95 (s, 2H), 4.21 (s,3H), 3.85 (s, 3H), 3.77-3.81 (m, 4H), 3.45-3.50 (m, 4H), 2.28 (s, 3H).

Example 983-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)oxazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

98A. Ethyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)oxazole-4-carboxylate

To a solution of 8-oxa-3-azabicyclo[3.2.1]octane (0.292 mL, 2.65 mmol)in THF (10 mL) was added ethyl 2-bromooxazole-4-carboxylate (0.583 g,2.65 mmol) followed by DIEA (0.926 mL, 5.30 mmol). The mixture washeated to reflux for 18 h under N₂. The cooled reaction mixture was thenconcentrated under reduced pressure and the crude residue was purifiedon the ISCO using a REDISEP® 24 g column (0 to 45% EtOAc-DCM) to givethe desired product as a pale yellow solid (0.592 g, 89%). LCMS (APCI):calcd for C₁₂H_(r)N₂O₄ [M+H]⁺ m/z 253.11, found 253.1. ¹H NMR (CDCl₃,400 MHz) δ ppm: 7.78 (s, 1H), 4.43 (d, J=2.2 Hz, 2H), 4.35 (q, J=7.2 Hz,2H), 3.66 (d, J=12.4 Hz, 2H), 3.34 (dd, J=12.3, 2.2 Hz, 2H), 1.92-2.04(m, 2H), 1.84-1.92 (m, 2H), 1.36 (t, J=7.0 Hz, 3H).

98B. (2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)oxazol-4-yl)methanol

The title compound was prepared from ethyl2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)oxazole-4-carboxylate accordingto the method described in Example 92B. The crude product mixture waspurified on the ISCO using a REDISEP® 4 g column (0 to 15% MeOH-DCM) andthe obtained material was suspended in MeOH, sonicated, filtered anddried to give the desired product as a white solid (0.382 g, 77%). LCMS(APCI): calcd for C₁₀H₁₅N₂O₃ [M+H]⁺ m/z 211.11, found 211.1. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.35 (s, 1H), 4.98 (t, J=5.5 Hz, 1H), 4.34-4.40(m, 2H), 4.20 (d, J=5.5 Hz, 2H), 3.45 (d, J=12.1 Hz, 2H), 3.10 (dd,J=12.1, 2.3 Hz, 2H), 1.79-1.89 (m, 2H), 1.71-1.79 (m, 2H).

Example 983-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)oxazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

The title compound was prepared according to the procedure described forthe synthesis of Example 92B. The crude product mixture was purified onthe ISCO using a REDISEP® Gold 12 g column (0 to 80% EtOAc-DCM) and theobtained material was suspended again in CH₃CN, sonicated, filtered anddried to give the title compound as a white solid (0.046 g, 41%). LC(Method C): 2.218 min. LCMS (APCI): calcd for C₂₄H₂₄N₅O₆S [M+H]⁺ m/z510.15, found 510.2. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.30 (s, 1H), 7.66(s, 1H), 6.87 (s, 1H), 6.75 (s, 1H), 6.52 (d, J=1.6 Hz, 1H), 4.89 (s,2H), 4.32 (br s, 2H), 4.14 (s, 3H), 3.74 (s, 3H), 3.43 (d, J=12.1 Hz,2H), 3.09 (dd, J=12.1, 2.0 Hz, 2H), 1.74-1.84 (m, 2H), 1.66-1.74 (m,2H).

Example 99 tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperazine-1-carboxylate

99A. Methyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (3.77 g, 20.26mmol) in MeOH (40 mL) was added methyl 2-bromothiazole-4-carboxylate(1.50 g, 6.75 mmol), followed by DIEA (6.25 mL, 35.8 mmol). The mixturewas then heated to reflux for 18 h under N₂. The cooled mixture was thenconcentrated under reduced pressure and the residue was purified on theISCO using a REDISEP® 40 g column (0 to 30% EtOAc-DCM) to give theproduct as a cream solid (0.579 g, 26%). LCMS (APCI): calcd forC₁₄H₂₂N₃O₄S [M+H]⁺ m/z 328.13, found 328.2. ¹H NMR (CDCl₃, 400 MHz) δppm: 7.50 (s, 1H), 3.90 (s, 3H), 3.55 (br s, 8H), 1.47-1.51 (m, 9H).

99B. Methyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate

The compound was prepared according to the procedure described inExample 92. The crude product was purified on the ISCO using a REDISEP®24 g column (0 to 20% MeOH-DCM) to give the title compound as a whitefoam (0.494 g, 93%). LCMS (APCI): calcd for C₁₃H₂₂N₃O₃S [M+H]⁺ m/z300.13, found 300.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 6.45 (s, 1H), 4.56(br s, 2H), 3.53-3.61 (m, 4H), 3.49 (br s, 4H), 3.35-3.44 (m, 1H), 1.49(s, 9H).

Example 99 tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperazine-1-carboxylate

The title compound was prepared according to the procedure described inExample 86 and was isolated as an off-white solid (0.339 g, 38%). LC(Method C): 1.602 min. HRMS(ESI): calcd for C₂₇H₃₁N₆O₆S₂ [M+H]⁺ m/z599.175, found 599.177. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.85 (s, 1H),7.10 (s, 1H), 6.70 (s, 1H), 6.64 (s, 1H), 6.44 (d, J=2.0 Hz, 1H), 5.16(s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.59 (d, J=5.5 Hz, 4H), 3.55 (br s,4H), 1.49 (s, 9H).

Example 1002-Methoxy-6-(6-methoxy-4-((2-(4-(methylsulfonyl)piperazin-1-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

100A. Methyl 2-(4-(methylsulfonyl)piperazin-1-yl)thiazole-4-carboxylate

To a solution of methyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate (0.20 g,0.61 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL, 26 mmol).The resulting mixture was stirred at room temperature for 3 h and thenit was concentrated under reduced pressure and the crude residue used assuch in the next step. The resulting methyl2-(piperazin-1-yl)thiazole-4-carboxylate TFA salt (0.32 g, 0.94 mmol)was dissolved in DCM (10 mL), treated with triethylamine (1.10 mL, 7.92mmol) and stirred at 25° C. for 5 min. The mixture was then cooled at 0°C. and methanesulfonyl chloride (0.10 mL, 1.29 mmol) was added and themixture was stirred at 0° C. for 4 h before being allowed to stirovernight at 25° C. The reaction mixture was then diluted with DCM andwashed with saturated aqueous NaHCO₃ and brine, dried over MgSO₄ andevaporated. The residue was purified on the ISCO using a REDISEP® 24 gcolumn (0 to 35% EtOAc-DCM) to give the desired product as a white solid(0.281, 98%). LCMS (APCI): calcd for C₁₀H₁₆N₃O₄S₂ [M+H]⁺ m/z 306.06,found 306.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.49-7.53 (m, 1H), 3.85-3.91(m, 3H), 3.63-3.72 (m, 4H), 3.30-3.39 (m, 4H), 2.80 (s, 3H).

100B. (2-(4-(Methylsulfonyl)piperazin-1-yl)thiazol-4-yl)methanol

The compound was prepared according to the procedure described inExample 92B. The crude product was purified on the ISCO using a REDISEP®24 g column (0 to 20% MeOH-DCM) to give the title compound as a whitefoam (0.215 g, 84%). LCMS (APCI): calcd for C₉H₁₆N₃O₃S₂ [M+H]⁺ m/z278.06, found 278.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 6.50 (s, 1H), 4.59(s, 2H), 3.80 (br s, 3H), 3.55-3.69 (m, 1H), 3.39-3.48 (m, 4H),3.33-3.39 (m, 1H), 2.80-2.88 (m, 3H).

Example 1002-Methoxy-6-(6-methoxy-4-((2-(4-(methylsulfonyl)piperazin-1-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared and purified according to the methoddescribed in Example 86 and was isolated as an off-white solid (0.038 g,30%). LC (Method C): 2.225 min. HRMS(ESI): calcd for C₂₃H₂₅N₆O₆S₃ [M+H]⁺m/z 577.0998, found 577.1017. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.37 (s,1H), 7.00 (s, 1H), 6.98 (s, 1H), 6.82 (d, J=0.8 Hz, 1H), 6.57 (d, J=1.6Hz, 1H), 5.07 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 3.51-3.58 (m, 4H),3.21-3.28 (m, 4H), 2.92 (s, 3H).

Example 1014-((4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)benzonitrile

101A. Methyl2-(4-((4-cyanophenyl)sulfonyl)piperazin-1-yl)thiazole-4-carboxylate

The compound was prepared using the procedure described in Example 100Aabove. The crude product was purified on the ISCO using a REDISEP® 24 gcolumn (0 to 40% EtOAc-DCM) to give the desired product as a white solid(0.222 g, 93%). LCMS (APCI): calcd for C₁₆H_(r)N₄O₄S₂ [M+H]⁺ m/z 393.07,found 393.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.83-7.93 (m, 4H), 7.50 (s,1H), 3.87-3.91 (m, 3H), 3.66-3.73 (m, 3H), 3.57-3.62 (m, 1H), 3.16-3.25(m, 4H).

101B.4-((4-(4-(hydroxymethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)benzonitrile

The compound was prepared according to the procedure described inExample 92B. The crude product was purified on the ISCO using a REDISEP®24 g column (0 to 15% MeOH-DCM) to give the desired product as a whitesolid (0.103 g, 50%). LCMS (APCI): calcd for C₁₅H₁₇N₄O₃S₂ [M+H]⁺ m/z365.06, found 365.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.83-7.95 (m, 4H),6.47 (s, 1H), 4.56 (s, 2H), 3.84 (br s, 3H), 3.54-3.67 (m, 1H),3.23-3.31 (m, 3H), 3.15-3.22 (m, 1H).

Example 1014-((4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperazin-lyl)sulfonyl)benzonitrile

The title compound was prepared according to the procedure described inExample 86. The crude product was purified on the ISCO using a REDISEP®4 g column (0 to 60% EtOAc-DCM) to give the title compound as a creamsolid (0.051 g, 41%). LC (Method C): 2.339 min. HRMS(ESI): calcd forC₂₉H₂₆N₇O₆S₃ [M+H]⁺ m/z 664.1107, found 664.1118. ¹H NMR (CDCl₃, 400MHz) δ ppm: 7.83-7.94 (m, 5H), 7.20 (s, 1H), 6.69 (s, 2H), 6.42 (d,J=2.0 Hz, 1H), 5.18 (s, 2H), 4.25 (s, 3H), 3.84 (s, 3H), 3.81 (br s,4H), 3.23-3.30 (m, 4H).

Example 1026-(4-((2-(4-(Isopropylsulfonyl)piperazin-1-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

102A. Methyl2-(4-(isopropylsulfonyl)piperazin-1-yl)thiazole-4-carboxylate

The compound was prepared according to the procedure described inExample 100A. The crude product was purified on the ISCO using aREDISEP® 24 g column (0 to 55% EtOAc-DCM) to give the desired product asa white solid (0.080 g, 56%). LCMS (APCI): calcd for C₁₂H₂₀N₃O₄S₂ [M+H]⁺m/z 334.08, found 334.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.53 (s, 1H),3.89-3.94 (m, 3H), 3.64-3.70 (m, 3H), 3.46-3.58 (m, 5H), 3.17-3.27 (m,1H), 1.37 (d, J=7.0 Hz, 6H).

102B. (2-(4-(Isopropylsulfonyl)piperazin-1-yl)thiazol-4-yl)methanol

The compound was prepared according to the procedure described inExample 92B. The crude product was purified on the ISCO using a REDISEP®4 g column (0 to 15% MeOH-DCM) to give the desired product as a whitefoam (0.070 g, 96%). LCMS (APCI): calcd for C₁₁H₂₀N₃O₃S₂ [M+H]⁺ m/z306.09, found 306.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 6.49 (s, 1H), 4.61(s, 1H), 4.53 (s, 1H), 3.81 (br s, 3H), 3.46-3.63 (m, 5H), 3.15-3.29 (m,1H), 1.61 (br s, 1H), 1.37 (d, J=6.7 Hz, 6H).

Example 1026-(4-((2-(4-(Isopropylsulfonyl)piperazin-1-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the procedure described inExample 86. The crude product was purified on the ISCO using a REDISEP®4 g column (0 to 60% EtOAc-DCM) to give title compound as a cream solid(0.082 g, 71%). LC (Method C): 2.266 min. HRMS(ESI): calcd forC₂₅H₂₉N₆O₆S₃ [M+H]⁺ m/z 605.1311, found 605.1327. ¹H NMR (CDCl₃, 400MHz) δ ppm: 8.36 (s, 1H), 6.98 (d, J=3.5 Hz, 2H), 6.80-6.84 (m, 1H),6.56 (d, J=2.0 Hz, 1H), 5.06 (s, 2H), 4.20 (s, 3H), 3.79 (s, 3H),3.45-3.50 (m, 4H), 3.36-3.39 (m, 4H), 3.29 (s, 1H), 1.23 (d, J=6.7 Hz,6H).

Example 1038-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane

103A. Methyl2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)thiazole-4-carboxylate

The compound was prepared according to the procedure described inExample 92A. The crude product was purified on the ISCO using a REDISEP®24 g column (0 to 55% EtOAc-DCM) to give the desired product as acolorless oil (0.416 g, 65%). LCMS (APCI): calcd for C₁₂H₁₇N₂O₄S [M+H]⁺m/z 285.09, found 285.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.46 (s, 1H),4.00 (s, 4H), 3.89 (s, 3H), 3.64-3.73 (m, 4H), 1.77-1.86 (m, 4H).

103B. (2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)thiazol-4-yl)methanol

The compound was prepared according to the procedure described inExample 92B. The crude product was purified on the ISCO using a REDISEP®4 g column (0 to 15% MeOH-DCM) to give the desired product as acolorless oil (0.124 g, 69%). LCMS (APCI): calcd for C₁₁H₁₇N₂O₃S [M+H]⁺m/z 257.10, found 257.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 6.39 (s, 1H),4.55 (br s, 2H), 3.99-4.02 (m, 5H), 3.65-3.73 (m, 4H), 1.81-1.88 (m,4H).

Example 1038-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane

The title compound was prepared according to the procedure described inExample 86. The crude product was purified on the ISCO using a REDISEP®4 g (0 to 50% EtOAc-DCM) to give the title compound as a cream solid(0.083 g, 38%). LC (Method C): 2.395 min. HRMS(ESI): calcd forC₂₅H₂₆N₅O₆S₂ [M+H]⁺ m/z 556.1325, found 556.1352. ¹H NMR (CDCl₃, 400MHz) δ ppm: 7.85 (s, 1H), 7.09 (s, 1H), 6.68-6.73 (m, 1H), 6.60 (s, 1H),6.46 (d, J=2.0 Hz, 1H), 5.25 (br s, 2H), 4.21 (s, 3H), 4.01 (s, 4H),3.83-3.86 (m, 3H), 3.78 (br. s., 3H), 1.84-1.92 (m, 4H).

Example 1046-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane

104A. Methyl 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazole-4-carboxylate

The compound was prepared according to the procedure described inExample 92A. The crude product was purified on the ISCO using a REDISEP®24 g column (0 to 100% EtOAc-DCM) to give the desired product as a whitesolid (0.145 g, 34%). LCMS (APCI): calcd for C₁₀H₁₃N₂O₃S [M+H]⁺ m/z241.06, found 241.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.51 (s, 1H), 4.85(s, 4H), 4.30 (s, 4H), 3.90 (s, 3H).

104B. (2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)thiazol-4-yl)methanol

The compound was prepared according to the procedure described inExample 92B. The reaction mixture was quenched with MeOH (10 mL) andstirred at room temperature for 10 min. Then the mixture wasconcentrated under reduced pressure, dissolved in DCM and washed withaqueous NaHCO₃, water and brine, dried over MgSO₄ and evaporated. Theproduct was isolated as a white gum (0.053 g, 41%). ¹H NMR (CDCl₃, 400MHz) δ ppm: 6.45-6.47 (m, 1H), 4.85-4.86 (m, 4H), 4.56 (d, J=6.1 Hz,2H), 4.24 (s, 4H), 2.11 (t, J=6.1 Hz, 1H).

Example 1046-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane

The title compound was prepared according to the procedure described inExample 86. The crude product was purified on the ISCO using a REDISEP®4 g column (0 to 100% EtOAc-DCM) to give the title compound as a whitesolid (0.070 g, 62%). LC (Method C): 2.081 min. HRMS(ESI): calcd forC₂₃H₂₂N₅O₅S₂ [M+H]⁺ m/z 512.1062, found 512.1067. ¹H NMR (CDCl₃, 400MHz) δ ppm: 7.85 (s, 1H), 7.09 (s, 1H), 6.70 (s, 1H), 6.63 (s, 1H), 6.41(d, J=2.0 Hz, 1H), 5.12 (s, 2H), 4.87 (s, 4H), 4.27 (s, 4H), 4.22 (s,3H), 3.84 (s, 3H).

Example 1054-(5-Ethyl-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)morpholine

105A. Methyl 5-ethyl-2-morpholinothiazole-4-carboxylate

The compound was prepared according to the procedure described inExample 92A. The crude product was purified on the ISCO using a REDISEP®12 g column (0 to 50% EtOAc-DCM) to give the desired product as a whitesolid (0.349 g, 68%). LCMS (APCI): calcd for C₁₁H_(r)N₂O₃S [M+H]⁺ m/z257.09, found 257.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 3.88 (s, 3H),3.75-3.85 (m, 4H), 3.41-3.50 (m, 4H), 3.14 (q, J=7.6 Hz, 2H), 1.27 (t,J=7.4 Hz, 3H).

105B. (5-Ethyl-2-morpholinothiazol-4-yl)methanol

The compound was prepared according to the procedure described inExample 92B. The reaction mixture was quenched with MeOH (10 mL) andstirred at room temperature for 10 min. Then the mixture wasconcentrated under reduced pressure, diluted with DCM, washed withNaHCO₃, water and brine, dried over MgSO₄ and evaporated. The residuewas purified on the ISCO using a REDISEP® 12 g column (0 to 15%MeOH-DCM) to give the desired product as a white solid (0.235 g, 76%).LCMS (APCI): calcd for C₁₀H₁₇N₂O₂S [M+H]⁺ 1229.10, found 229.1. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 4.48 (d, J=5.9 Hz, 2H), 3.77-3.85 (m, 4H),3.37-3.46 (m, 4H), 2.68 (q, J=7.4 Hz, 2H), 2.25 (t, J=5.9 Hz, 1H), 1.22(t, J=7.4 Hz, 3H).

Example 1054-(5-Ethyl-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)morpholine

The title compound was prepared according to the procedure described forthe synthesis of Example 86. The crude product was purified on the ISCOusing a REDISEP® 4 g column (0 to 60% EtOAc-DCM) and the obtained solidwas suspended in CH₃CN, sonicated, filtered and dried to give the titlecompound as an off-white solid (0.086 g, 74%). LC (Method C): 2.263 min.HRMS(ESI): calcd for C₂₄H₂₆N₅O₅S₂ [M+H]⁺ m/z 528.1375, found 528.1374.¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.83 (s, 1H), 7.04 (s, 1H), 6.69 (dd,J=2.0, 0.8 Hz, 1H), 6.52 (d, J=2.0 Hz, 1H), 5.05 (s, 2H), 4.21 (s, 3H),3.85 (s, 3H), 3.79-3.84 (m, 4H), 3.42-3.47 (m, 4H), 2.78 (q, J=7.6 Hz,2H), 1.23 (t, J=7.6 Hz, 3H).

Example 1063-((4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)(methyl)amino)propanenitrile

106A. Methyl 2-((2-cyanoethyl)(methyl)amino)thiazole-4-carboxylate

In a sealable tube, a solution of methyl 2-bromothiazole-4-carboxylate(0.500 g, 2.252 mmol) and 3-(methylamino)propanenitrile (0.176 mL, 1.876mmol) in dioxane (8 mL) was treated with cesium carbonate (0.611 g,1.876 mmol), palladium(II) acetate (0.021 g, 0.094 mmol) and Xantphos(0.065 g, 0.113 mmol). The system was purged with nitrogen for 5 min andthen the tube was sealed and the mixture heated at 100° C. for 16h. Thecooled reaction mixture was then partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate. The organic phase was washed withbrine, dried over anhydrous magnesium sulfate and concentrated in vacuo.The residue obtained was chromatographed on silica gel (ISCO, elutiongradient of methanol in dichloromethane) to give 0.300 g (59%) of thetitle compound. LC (Method B): 1.927 min. LCMS (APCI): calcd forC₉H₁₂N₃O₂S [M+H]⁺ m/z 226.07, found 226.0.

106B. 3-((4-(Hydroxymethyl)thiazol-2-yl)(methyl)amino)propanenitrile

A solution of methyl2-((2-cyanoethyl)(methyl)amino)thiazole-4-carboxylate (0.300 g, 1.332mmol) in ethanol (5 mL) at 0° C. was treated with sodium borohydride(0.151 g, 4.00 mmol), followed by calcium chloride (0.177 g, 1.598 mmol)and then stirred at room temperature for 4 h. The reaction mixture wasthen partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate, the organic phase was separated, washed with brine, driedover anhydrous magnesium sulfate and concentrated in vacuo. The residueobtained was chromatographed on silica gel (ISCO, elution gradient ofethyl acetate in dichloromethane) to give 0.048 g (18%) of the titlematerial as an oil which crystallized on standing to give a white solid.LC (Method B): 1.376 min. LCMS (APCI): calcd for C₈H₁₂N₃OS [M+H]⁺ m/z198.07; found 198.0. ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.43 (s, 1H), 4.52(s, 2H), 3.80 (t, J=6.55 Hz, 2H), 3.18 (br s, 1H), 3.15 (s, 3H), 2.73(t, J=6.55 Hz, 2H).

Example 1063-((4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)(methyl)amino)propanenitrile

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.064 g, 0.203 mmol) and3-((4-(hydroxymethyl)thiazol-2-yl)(methyl)-amino)propanenitrile (0.048g, 0.243 mmol) in dry THF (3.5 mL) under nitrogen was treated at 22° C.with tri-n-butylphosphine (0.132 mL, 0.507 mmol), followed by a solutionof 1,1′-(azodicarbonyl)dipiperidine (0.129 g, 0.507 mmol) in dry THF(2.5 mL) added dropwise (via syringe pump) over 1 h. The resulting beigesuspension was stirred for an additional 1 h and then it was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic phase was separated, washed with brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue obtained waschromatographed on silica gel (ISCO, elution gradient of ethyl acetatein dichloromethane) to give 0.085 g (85%) of the title compound as awhite solid. LC (Method A): 2.179 min. HRMS(ESI): calcd for C₂₂H₂₁N₆O₄S₂[M+H]⁺ m/z 497.1066; found: 497.1113. ¹H NMR (400 MHz, CDCl₃) δ ppm:7.85 (s, 1H), 7.09 (s, 1H), 6.68-6.72 (m, 1H), 6.62 (br s, 1H), 6.46 (d,J=1.96 Hz, 1H), 5.11 (s, 2H), 4.21 (s, 3H), 3.82-3.89 (m, 5H), 3.20 (s,3H), 2.80 (t, J=6.46 Hz, 2H).

Example 107(S)-2-Methoxy-6-(6-methoxy-4-((2-(2-(methoxymethyl)pyrrolidin-1-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

107A.(S)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(2-(methoxymethyl)pyrrolidin-1-yl)thiazole

A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 0.500 g, 1.622 mmol) and (S)-2-(methoxymethyl)pyrrolidine(0.224 g, 1.946 mmol) in 1,4-dioxane (5 mL) was treated withtriethylamine (0.678 mL, 4.87 mmol) and the resulting mixture was heatedat 100° C. for 18 h. The cooled reaction mixture was concentrated invacuo and the residue was chromatographed on silica gel (ISCO, elutiongradient of ethyl acetate in dichloromethane) to give 0.175 g (31%) ofthe title material. LC (Method B): 2.685 min. LCMS (APCI): calcd forC₁₆H₃₁N₂O₂SSi [M+H]⁺ m/z 343.19; found 343.2. ¹H NMR (400 MHz, CDCl₃) δppm: 6.35 (s, 1H), 4.68 (s, 2H), 4.02 (dt, J=6.65, 3.33 Hz, 1H), 3.61(dd, J=9.39, 3.4 Hz, 1H), 3.40-3.56 (m, 2H), 3.28-3.39 (m, 4H),1.91-2.16 (m, 4H), 0.95 (s, 9H), 0.12 (s, 6H).

107B. (S)-(2-(2-(Methoxymethyl)pyrrolidin-1-yl)thiazol-4-yl)methanol

The title compound was prepared according to the deprotection proceduredescribed in Example 93C. LC (Method B): 1.431 min. LCMS (APCI): calcdfor C₁₀H₁₇N₂O₂S [M+H]⁺ m/z 229.10; found 229.2. ¹H NMR (400 MHz, CDCl₃)δ ppm: 6.33 (s, 1H), 4.54 (s, 2H), 3.96-4.08 (m, 1H), 3.38-3.63 (m, 4H),3.27-3.37 (m, 4H), 1.92-2.19 (m, 4H).

Example 107(S)-2-Methoxy-6-(6-methoxy-4-((2-(2-(methoxymethyl)pyrrolidin-1-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the general couplingprocedure described in Example 106. LC (Method A): 2.090 min. HRMS(ESI):calcd for C₂₄H₂₆N₅O₅S₂ [M+H]⁺ m/z 528.1375; found 528.1352. ¹H NMR (400MHz, CDCl₃) δ ppm: 7.83 (s, 1H), 7.10 (s, 1H), 6.69 (s, 1H), 6.53 (s,1H), 6.45 (s, 1H), 5.13 (s, 2H), 4.19 (s, 3H), 4.05 (br s, 1H), 3.84 (s,3H), 3.58-3.66 (m, 1H), 3.43-3.58 (m, 2H), 3.31-3.43 (m, 4H), 1.94-2.19(m, 4H).

Example 108N-(4-Bromo-2-methylphenyl)-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-amine

108A. Ethyl2-((4-bromo-2-methylphenyl)(tert-butoxycarbonyl)amino)thiazole-4-carboxylate

A suspension of ethyl2-((4-bromo-2-methylphenyl)amino)thiazole-4-carboxylate (0.083 g, 0.243mmol; obtained by the condensation of 1-(4-bromo-2-methylphenyl)thioureawith ethyl bromopyruvate) in THF (2 mL) was treated, under nitrogen,with di-tert-butyl dicarbonate (0.169 mL, 0.730 mmol), DMAP (0.015 g,0.122 mmol) and triethylamine (0.102 mL, 0.730 mmol). The mixture wasstirred for 3 h at room temperature before being concentrated underreduced pressure. The obtained solid residue was purified on the ISCOusing a REDISEP® Gold 12 g column (elution with hexanes-EtOAc) to givethe title material (0.080 g, 74.5%) as a solid. LC (Method F): 2.341min. LCMS (APCI) calcd for C₁₈H₂₂BrN₂O₄S [M+H]⁺ m/z 441.05, found 441.2.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.82 (s, 1 H), 7.45 (d, J=2.0 Hz, 1 H),7.40 (dd, J=8.2, 2.3 Hz, 1 H), 7.06 (d, J=8.2 Hz, 1 H), 4.28 (q, J=7.2Hz, 2 H), 2.09 (s, 3 H), 1.44 (s, 9 H), 1.32 (t, J=7.0 Hz, 3 H).

108B. tert-Butyl(4-bromo-2-methylphenyl)(4-(hydroxymethyl)thiazol-2-yl)carbamate

An ice-cold solution of ethyl2-((4-bromo-2-methylphenyl)(tert-butoxycarbonyl)amino)-thiazole-4-carboxylate(0.080 g, 0.181 mmol) in THF (3 mL) under nitrogen was treated withNaBH₄ (0.0274 g, 0.725 mmol) and methanol (0.147 mL, 3.63 mmol). After30 min, the ice bath was removed and the reaction was stirred at roomtemperature for 5.5 h. At this point, more NaBH₄ (0.013 g) and methanol(0.3 mL) were added and stirring was continued for 30 min. The resultingturbid solution was cooled in an ice bath and quenched with acetic acid(0.5 mL). The reaction mixture was diluted with ethyl acetate (40 mL),washed with saturated aqueous sodium bicarbonate (2×20 mL) and brine (20mL) and then dried over anhydrous magnesium sulfate. Evaporation of thesolvent gave a foamy residue which was purified on the ISCO using aREDISEP® Gold 4 g column (elution with hexanes-EtOAc) to give titlematerial (0.064 g, 88%). LC (Method F): 2.216 min. LCMS (APCI): calcdfor C₁₆H₂₀BrN₂O₃S [M+H]⁺ m/z 399.04, found 399.0. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.45 (d, J=2.3 Hz, 1 H), 7.40 (dd, J=8.4, 2.2 Hz, 1 H),7.02 (d, J=8.6 Hz, 1 H), 6.81 (s, 1 H), 4.49 (d, J=6.3 Hz, 2 H), 2.09(s, 3 H), 1.96 (t, J=6.3 Hz, 1 H), 1.44 (s, 9 H).

108C. tert-Butyl(4-bromo-2-methylphenyl)(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)carbamate

To solid6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.045 g, 0.142 mmol) was added, at room temperature undernitrogen, tert-butyl(4-bromo-2-methylphenyl)(4-(hydroxymethyl)thiazol-2-yl)carbamate (0.062g, 0.156 mmol) and tri-n-butylphosphine (0.175 mL, 0.709 mmol) and themixture was pumped under high vacuum for 20 min. Anhydrous THF (3 mL)was then added, followed by the dropwise addition of a solution of1,1′-(azodicarbonyl)dipiperidine (0.089 g, 0.355 mmol) in THF (3 mL),dropwise over 20 min. The mixture was stirred at room temperature foranother 3 h, before being diluted with dichloromethane (75 mL), washedwith saturated aqueous NaHCO₃ (2×20 mL), water (20 mL) and brine (20mL), and finally dried (MgSO₄). Evaporation of the solvent gave asemi-solid which was purified on the ISCO using a REDISEP® Gold 24 gcolumn (elution with hexanes-EtOAc) to give a solid that was furthertriturated with acetonitrile (1 mL) and lyophilized to give the titlecompound (0.088 g, 89%) as a solid. LC (Method F): 2.630 min. HRMS(ESI):calcd for C₃₀H₂₉BrN₅O₆S₂ [M+H]⁺ m/z 698.0743, found 698.0753. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 8.36 (s, 1 H), 7.59 (d, J=2.0 Hz, 1 H), 7.48(dd, J=8.4, 2.2 Hz, 1 H), 7.40 (s, 1 H), 7.25 (d, J=8.2 Hz, 1 H),6.89-6.94 (m, 1 H), 6.79 (s, 1 H), 6.48 (d, J=1.6 Hz, 1 H), 5.02 (s, 2H), 4.21 (s, 3 H), 3.77 (s, 3 H), 2.00 (s, 3 H), 1.37 (s, 9 H).

Example 108N-(4-Bromo-2-methylphenyl)-4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-amine

To a solution of tert-butyl(4-bromo-2-methylphenyl)(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)carbamate(0.030 g, 0.043 mmol) in dichloromethane (4 mL) was added a 95% solutionof TFA (0.5 mL) in water. The mixture was stirred at room temperaturefor 3 h, then toluene (5 mL) was added and the mixture was concentrated.Toluene (5 mL) was added to the concentrate and the volatiles wereevaporated to give a solid, which was subsequently triturated withacetonitrile (1 mL). The mixture was filtered and the obtained solid waslyophilized from MeCN-water to give the title compound (0.025 g, 97%) asa white powder. LC (Method F): 2.535 min. HRMS(ESI): calcd forC₂₅H₂₁BrN₅O₄S₂ [M+H]⁺ m/z 598.0218, found 598.0214. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 9.37 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.40(d, J=2.0 Hz, H), 7.33 (dd, J=8.6, 2.3 Hz, 1H), 6.98 (d, J=7.4 Hz, 2H),6.83 (d, J=1.2 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 5.11 (s, 2H), 4.20 (s,3H), 3.80 (s, 3H), 2.26 (s, 3H).

Example 109 tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidine-1-carboxylate

109A. Ethyl2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylate

To a suspension of tert-butyl 4-carbamothioylpiperidine-1-carboxylate(1.50 g, 6.14 mmol) in ethanol (6 mL) at 0° C. was added dropwise asolution of ethyl 3-bromo-2-oxopropanoate (0.788 mL, 6.26 mmol) inethanol (6 mL). The ice bath was then removed and the reaction mixturewas stirred at ambient temperature overnight. Triethylamine (1.5 mL,10.76 mmol) was then added and the mixture was concentrated to neardryness and the concentrate was diluted with ethyl acetate, washed withbrine, dried (MgSO₄) and evaporated to dryness. The residue was purifiedby flash chromatography using hexanes-ethyl acetate as eluent to giveethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylate(1.55 g, 74.2%) as a nearly colorless oil that crystallized on standingto give a white solid. LC (Method A): 2.115 min. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 8.42 (s, 1H), 7.20 (br s, 2H), 4.29 (q, J=7.0 Hz, 2H), 4.00(m, 1H), 3.24 (m, 1H), 2.88 (br s, 1H), 2.03 (m, 2H), 1.54 (m, 2H), 1.29(t, J=7.2 Hz, 3H).

109B. tert-Butyl4-(4-(hydroxymethyl)thiazol-2-yl)piperidine-1-carboxylate

To a stirred solution of ethyl2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylate (1.430g, 4.20 mmol) in THF (21 mL) at ambient temperature was added lithiumborohydride (0.183 g, 8.40 mmol), followed by MeOH (0.340 mL, 8.40mmol). The resulting mixture was stirred at room temperature for 16 hbefore being quenched with saturated aqueous NH₄Cl and extracted withEtOAc. The organic phase was separated, dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by flashchromatography using DCM-EtOAc as eluent to give the product as a clear,colorless oil. This oil was taken up in acetonitrile-water andlyophilized to give tert-butyl4-(4-(hydroxymethyl)thiazol-2-yl)piperidine-1-carboxylate (0.996 g, 79%)as a white solid. LC (Method A): 1.875 min. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 7.27 (m, 1H), 5.26 (t, J=5.2 Hz, 1H), 4.52 (d, J=4.7 Hz, 2H), 3.99(d, J=11.3 Hz, 2H), 3.15 (m, 1H), 2.87 (br s, 2H), 2.00 (m, 2H), 1.51(m, 2H), 1.40 (s, 9H).

Example 109 tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidine-1-carboxylate

To a suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.339 g, 1.069 mmol) and tert-butyl4-(4-(hydroxymethyl)thiazol-2-yl)piperidine-1-carboxylate (0.319 g,1.069 mmol) in dry THF (8 mL) was added tri-n-butylphosphine (0.694 mL,2.67 mmol), followed by a solution of ADDP (0.674 g, 2.67 mmol) in THF(2 mL) added dropwise over 30 min via syringe pump. After stirring foranother 30 min, the reaction mixture was partitioned between EtOAc andsaturated aqueous NaHCO₃. The organic phase was separated, washed withbrine, dried (MgSO₄), filtered and concentrated to dryness. The residuewas purified by flash chromatography using DCM-EtOAc as eluent to givethe title compound (0.432 g, 67.6%) as a white solid. LC (Method A):2.479 min. HRMS(ESI): calcd for C₂₈H₃₂N₅O₆S₂ [M+H]⁺ m/z 598.1794, found598.1806. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.70 (s, 1H),6.98 (d, J=0.8 Hz, 1H), 6.83 (dd, J=0.8, 1.6 Hz, 1H), 6.61 (d, J=2.0 Hz,1H), 5.26 (s, 2H), 4.20 (s, 3H), 4.00 (m, 2H), 3.80 (s, 3H), 3.22 (m,1H), 2.90 (br s, 1H), 2.04 (m, 2H), 1.55 (m, 2H), 1.40 (s, 9H).

Example 110(4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidin-1-yl)(phenyl)methanone

To a stirred suspension of tert-butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidine-1-carboxylate(0.406 g, 0.679 mmol) in DCM (8 mL) was added TFA (1 mL) and the mixturewas stirred at room temperature for 4 h, before being concentrated todryness. The residue was partitioned with EtOAc-saturated aqueous NaHCO₃and the organic phase was separated, dried with MgSO₄, filtered andconcentrated to dryness to give2-methoxy-6-(6-methoxy-4-(2-(piperidin-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(TFA salt, 0.415 g, 100%) as a beige solid. LC (Method A): 1.990 min.LCMS (APCI): calcd for C₂₃H₂₄N₅O₄S₂ [M+H]⁺ m/z 498.13. found 498.20.

To a stirred solution of2-methoxy-6-(6-methoxy-4-((2-(piperidin-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(0.025 g, 0.050 mmol) in DMF (1 mL) was added DIEA (0.044 mL, 0.250mmol) and benzoic acid (0.0067 g, 0.055 mmol), followed by HATU (0.021g, 0.055 mmol). The reaction mixture was stirred for 1 h, before beingdiluted with DMF (1 mL) and submitted directly to purification bypreparative HPLC (Method A). Product-containing fractions wereconcentrated to dryness and the residue was lyophilized from MeCN-waterto give the title compound (0.012 g, 39.9%) as an amorphous white solid.LC (Method A): 2.328 min. HRMS(ESI): calcd for C₃₀H₂₈N₅O₅S₂ [M+H]⁺ m/z602.1532, found 602.1532. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H),7.72 (s, 1H), 7.46-7.39 (m, 5H), 6.98 (d, J=0.8 Hz, 1H), 6.83 (dd,J=0.8, 1.6 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 5.26 (s, 2H), 4.52 (br s,1H), 4.20 (s, 3H), 3.80 (s, 3H), 3.65 (br s, 1H), 3.08 (m, 3H), 2.10 (m,2H), 1.69 (m, 2H).

Example 1116-(4-((2-(1-(Isopropylsulfonyl)piperidin-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a stirred solution of2-methoxy-6-(6-methoxy-4-(2-(piperidin-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(0.025 g, 0.050 mmol) in DMF (1 mL) was added DIEA (0.044 mL, 0.250mmol) and propane-2-sulfonyl chloride (5.61 μl, 0.050 mmol). Thereaction mixture was stirred at room temperature for 1 h, before beingdiluted with DMF (1 mL) and purified by preparative HPLC (Method A).Product-containing fractions were concentrated to dryness and theresidue was lyophilized from MeCN-water to give the title compound(0.007 g, 0.012 mmol, 23.19%) as an amorphous white solid. LC (MethodA): 2.283 min. HRMS(ESI): calcd for C₂₆H₃₀N₅O₆S₃ [M+H]⁺ m/z 604.1358,found 604.1373. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.72 (s,1H), 6.98 (d, J=0.8 Hz, 1H), 6.83 (dd, J=0.8, 2.0 Hz, 1H), 6.61 (d,J=2.0 Hz, 1H), 5.27 (s, 2H), 4.20 (s, 3H), 3.81 (s, 3H), 3.72 (m, 2H),3.24 (m, 2H), 3.06 (m, 2H), 2.12 (m, 2H), 1.67 (m, 2H), 1.22 (d, J=7.0Hz, 6H).

Example 1122-Methoxy-6-(6-methoxy-4-((2-(1-(methylsulfonyl)piperidin-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 111 above and was isolated as a solid. LC (Method A): 2.172 min.HRMS(ESI): calcd for C₂₄H₂₆N₅O₆S₃ [M+H]⁺ m/z 576.1040, found 576.1041.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.73 (s, 1H), 6.99 (s,1H), 6.84 (dd, J=0.8, 1.6 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 5.27 (s, 2H),4.20 (s, 3H), 3.81 (s, 3H), 3.64 (m, 2H), 3.18 (m, 1H), 2.90 (m, 2H),2.89 (s, 3H), 2.18 (m, 2H), 1.75 (m, 2H).

Example 1132-Methoxy-6-(6-methoxy-4-((2-(1-(phenylsulfonyl)piperidin-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 111 above and was isolated as a solid. LC (Method A): 2.014 min.HRMS(ESI): calcd for C₂₉H₂₈N₅O₆S₃ [M+H]⁺ m/z 638.1202, found 638.1422.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.79-7.64 (m, 6H), 6.97(d, J=0.8 Hz, 1H), 6.83 (dd, J=0.8, 1.6 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H),5.23 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 3.71 (m, 2H), 3.06 (m, 1H),2.45 (m, 2H), 2.13 (m, 2H), 1.72 (m, 2H).

Example 1142-Methoxy-6-(6-methoxy-4-((2-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 111 above and was isolated as a solid. LC (Method A): 2.403 min.HRMS(ESI): calcd for C₂₄H₂₃F₃N₅O₆S₃ [M+H]⁺ m/z 630.0763, found 630.0821.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.74 (s, 1H), 6.98 (d,J=0.8 Hz, 1H), 6.84 (dd, J=0.8, 1.6 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H),5.27 (s, 2H), 4.20 (s, 3H), 3.89 (m, 2H), 3.80 (s, 3H), 2.23 (m, 2H),1.74 (m, 2H).

Example 1156-(4-((2-(4,4-Difluorocyclohexyl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

115A. 4,4-Difluorocyclohexanecarboxamide

To a stirred solution of 4,4-difluorocyclohexanecarboxylic acid (1.50 g,9.14 mmol) in DCM (22 mL) was added oxalyl chloride (1.600 mL, 18.28mmol) and the reaction mixture was stirred for 1 h at room temperaturebefore being evaporated to dryness. The residue was taken up in dry THF(4.5 mL) and was added with stirring to ice-cold concentrated aqueousammonia (22 mL). The mixture was stirred at 0° C. for 2 min and then atroom temperature for 30 min, before being diluted with water andextracted with EtOAc. The organic phase was dried (MgSO₄), filtered andconcentrated to dryness to give 4,4-difluorocyclohexanecarboxamide (1.02g, 68.4%) as a white solid. This material was used as such in the nextstep. LC (Method F): 2.567 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 7.29(br s, 1H), 6.79 (br s, 1H), 2.26-2.18 (m, 1H), 2.07-1.97 (m, 2H),1.86-1.70 (m, 4H), 1.62-1.51 (m, 2H).

115B. 4,4-Difluorocyclohexanecarbothioamide

To a solution of 4,4-difluorocyclohexanecarboxamide (1.00 g, 6.13 mmol)in THF (10 mL) was added Lawesson's reagent (1.239 g, 3.06 mmol) and themixture was heated in a sealed vessel at 65° C. for 6 h. The cooledmixture was partitioned between EtOAc-saturated aqueous NaHCO₃ and theorganic phase was washed with brine, dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by flashchromatography using hexanes-EtOAc as eluent to give4,4-difluorocyclohexanecarbothioamide (0.634 g, 3.54 mmol, 57.7%) as awhite solid. LC (Method F): 1.432 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:9.42 (br s, 1H), 9.15 (br s, 1H), 2.63 (m, 1H), 2.10-2.01 (m, 2H),1.90-1.80 (m, 1H), 1.79-1.72 (m, 5H).

115C. Ethyl 2-(4,4-difluorocyclohexyl)thiazole-4-carboxylate

A sealable vessel was charged with 4,4-difluorocyclohexanecarbothioamide(0.600 g, 3.35 mmol), ethyl bromopyruvate (0.505 mL, 4.02 mmol) andi-PrOH (15 mL) and the mixture was heated at 85° C. for 3 h. The cooledmixture was partitioned between EtOAc-saturated aqueous NaHCO₃ and theorganic phase was dried (MgSO₄), filtered and concentrated to dryness.The residue was purified by column chromatography using hexanes-EtOAc aseluent to give ethyl 2-(4,4-difluorocyclohexyl)thiazole-4-carboxylate(0.600 g, 2.179 mmol, 65.1%) as a white solid. LC (Method F): 2.089 min.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.43 (s, 1H), 4.29 (q, J=7.0 Hz, 2H),3.27 (m, 1H), 2.20-1.91 (m, 6H), 1.75 (m, 2H), 1.30 (t, J=7.2 Hz, 3H).

115D. (2-(4,4-Difluorocyclohexyl)thiazol-4-yl)methanol

To an ice-cold solution of ethyl2-(4,4-difluorocyclohexyl)thiazole-4-carboxylate (0.580 g, 2.107 mmol)in THF (11 mL) was added LiBH₄ (0.092 g, 4.20 mmol) all at once,followed by MeOH (0.170 mL, 4.20 mmol). The resulting mixture wasstirred at 0° C. for 5 min and then at ambient temperature for 4 h. Themixture was then cooled in an ice-bath, quenched by dropwise addition ofsaturated aqueous NH₄Cl and extracted with ethyl acetate. The organicphase was then washed with brine, dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by flashchromatography using a gradient of 0 to 100% EtOAc in hexanes to give(2-(4,4-difluorocyclohexyl)thiazol-4-yl)methanol (0.398 g, 81%) as aclear, colorless oil. LC (Method F): 1.776 min. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 7.28 (m, 1H), 5.26 (br s, 1H), 4.52 (s, 2H), 3.17 (m, 1H),2.14-1.90 (m, 6H), 1.78-1.67 (m, 2H).

Example 1156-(4-((2-(4,4-Difluorocyclohexyl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 109 and was isolated as a solid. LC (Method F): 2.556 min.HRMS(ESI): calcd for C₂₄H₂₃FN₄O₄S₂ [M+H]⁺ m/z 533.1145, found 533.1161.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.71 (s, 1H), 6.98 (m,1H), 6.61 (m, 1H), 5.28 (m, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 3.24 (m,1H), 2.18-1.92 (m, 6H), 1.76 (m, 2H).

Example 1165-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)isoxazole

116A. Ethyl 2-(isoxazol-5-yl)thiazole-4-carboxylate

To a suspension of isoxazole-5-carbothioamide (0.500 g, 3.90 mmol) inethanol (10 mL) was added ethyl 3-bromo-2-oxopropanoate (0.598 mL, 4.29mmol) and the resulting mixture was heated to 90° C. for 1.5 h. Thecooled reaction mixture was evaporated to dryness and the residue wasthen partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic phase was separated, washed with brine, driedover anhydrous magnesium sulfate and concentrated in vacuo. The residueobtained was chromatographed on silica gel (ISCO, elution gradient ofethyl acetate in dichloromethane) to give 0.800 g (92%) of the titlematerial as a reddish solid. LC (Method B): 2.167 min. LCMS (ESI):calcd. for C₉H₉N₂O₃S [M+H]⁺ m/z 225.03; found: 225.0. ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.36-8.42 (m, 1H), 8.28-8.34 (m, 1H), 6.94-7.10 (m, 1H),4.35-4.53 (m, 2H), 1.31-1.48 (m, 3H).

116B. (2-(Isoxazol-5-yl)thiazol-4-yl)methanol

A solution of ethyl 2-(isoxazol-5-yl)thiazole-4-carboxylate (0.087 g,0.388 mmol) in THF (2 mL) at 0° C. was treated with methanol (0.056 mL,1.395 mmol), followed by lithium borohydride (0.030 g, 1.395 mmol).After 15 min, the cooling bath was removed and the reaction mixture wasstirred at 22° C. for 3 h. The reaction mixture was then quenched withsaturated aqueous NH₄Cl and diluted with dichloromethane. The aqueousphase was separated and back-extracted (×3) with dichloromethane and thecombined organic extract was dried over MgSO₄ and evaporation underreduced pressure gave 0.039 g (56%) of the title material which was usedas such for next step. LC (Method B): 1.818 min. LCMS (APCI): calcd. forC₇H₇N₂O₂S [M+H]⁺ m/z 183.02; found: 183.0. ¹H NMR (400 MHz, CDCl₃) δppm: 8.36 (d, J=1.8 Hz, 1H), 7.41 (s, 1H), 6.87 (d, J=1.8 Hz, 1H), 4.87(d, J=5.4 Hz, 2H), 3.00 (t, J=5.4 Hz, 1H).

Example 1165-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)isoxazole

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.032 g, 0.100 mmol) and(2-(isoxazol-5-yl)thiazol-4-yl)methanol (0.020 g, 0.110 mmol) in dry THF(2.5 mL) under nitrogen was treated at 22° C. with tri-n-butylphosphine(0.065 mL, 0.249 mmol), followed by a solution of1,1′-(azodicarbonyl)dipiperidine (0.064 g, 0.249 mmol) in dry THF (2.5mL), added dropwise (via syringe pump) over 1 h. The resulting beigesuspension was stirred for an additional 1 h at room temperature andthen it was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The organic phase was separated, washed with brine,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresidue obtained was chromatographed on silica gel (ISCO, elutiongradient of ethyl acetate in dichloromethane) and the obtained materialwas triturated with methanol to give (after filtration and drying invacuo) 0.013 g (27%) of the title compound. LC (Method A): 2.289 min.HRMS(ESI): calcd for C₂₁H₁₆N₅O₅S₂ [M+H]⁺ m/z 482.0593; found: 482.0602.¹H NMR (400 MHz, CDCl₃) δ ppm: 8.38 (d, J=1.96 Hz, 1H), 7.86 (s, 1H),7.58 (s, 1H), 7.10 (s, 1H), 6.89 (d, J=1.96 Hz, 1H), 6.69-6.76 (m, 1H),6.43 (d, J=1.57 Hz, 1H), 5.37-5.45 (m, 2H), 4.21 (s, 3H), 3.85 (s, 3H).

Example 1175-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)oxazole

117A. Ethyl 2-(oxazol-5-yl)thiazole-4-carboxylate

Oxazole-5-carbothioamide (0.390 g, 3.04 mmol) was reacted with ethyl3-bromo-2-oxopropanoate (0.263 mL, 1.884 mmol) as described in Example116A above to give 0.085 g (22%) of the title material. LC (Method B):1.811 min. LCMS (APCI): calcd for C₉H₉N₂O₃S [M+H]⁺ m/z 225.03; found:225.0. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.21 (s, 1H), 7.98 (s, 1H), 7.80(s, 1H), 4.44 (q, J=7.04 Hz, 2H), 1.41 (t, J=7.04 Hz, 3H).

117B. (2-(Oxazol-5-yl)thiazol-4-yl)methanol

Ethyl 2-(oxazol-5-yl)thiazole-4-carboxylate (0.112 g, 0.499 mmol) wastreated with lithium borohydride (0.022 g, 0.999 mmol) as described inExample 116B above to give 0.024 g (26%) of the title compound afterflash chromatography. LC (Method B): 1.462 min. HRMS(ESI): calcd forC₇H₇N₂O₂S [M+H]⁺ m/z 183.0228; found 183.0222. ¹H NMR (400 MHz, CDCl₃) δppm: 7.99 (s, 1H), 7.80 (s, 1H), 7.32 (s, 1H), 4.86 (s, 2H), 2.90(br s,1H).

Example 1175-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)oxazole

Reaction of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.079 g, 0.249 mmol) with(2-(oxazol-5-yl)thiazol-4-yl)methanol (0.050 g, 0.274 mmol), asdescribed in Example 116 above, gave 0.035 g (29%) of the title compoundas a beige solid. LC (Method A): 2.278 min. HRMS(ESI): calcd forC₂₁H₁₆N₅O₅S₂[M+H]⁺ m/z 482.0593; found 482.0595. ¹H NMR (400 MHz, CDCl₃)δ ppm: 7.98 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.11 (s,1H), 6.72 (br d, 1H), 6.44 (d, J=1.96 Hz, 1H), 5.39 (s, 2H), 4.22 (s,3H), 3.85 (s, 3H).

Example 1184-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

118A.4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 3.39 g, 11.00 mmol) in dry THF (55 mL) was cooled at −78°C. under N₂ and then 1.45 M n-butyllithium (9.10 mL, 13.20 mmol) wasadded dropwise. The resulting mixture was stirred for 30 min to give apale brown solution. To this mixture was slowly added a solution ofdihydro-2H-pyran-4(3H)-one (1.219 mL, 13.20 mmol) in dry THF (5 mL) andthe mixture was kept at −78° C. for 1 h, to give a pale brown solution.The reaction was quenched by the addition of saturated aqueous NH₄Cl (15mL) and then the cooling bath was removed and the mixture waspartitioned with EtOAc-water. The organic phase was separated, washed(brine), dried (Na₂SO₄) and evaporated to give a pale yellow oil. Flashchromatography (Isco/0-30% acetone-hexane) afforded4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol(2.97 g, 82%) as a colorless oil which crystallized on standing invacuo. LC (Method A): 2.262 min. HRMS(ESI): calcd for C₁₅H₂₈NO₃SSi[M+H]⁺ m/z 330.156; found 330.158. ¹H NMR (400 MHz, DMSO-d₆): δ 7.23 (s,1H), 5.99 (s, 1H), 4.64 (s, 2H), 3.64 (m, 4H), 2.00 (ddd, J=5.48, 11.35,13.69 Hz, 2H), 1.56 (br d, J=12.91 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H).

118B. 4-(4-(Hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

To a solution of4-(4-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol(2.96 g, 8.98 mmol) in dry THF (40 mL) under N₂ was added triethylaminetrihydrofluoride (3.66 mL, 22.46 mmol) dropwise and the mixture wasstirred at room temperature for 16 h. The mixture was then concentratedto half volume and the concentrate was diluted with DCM and thensaturated aqueous NaHCO₃ was added (Caution: vigorous gas evolution!).The organic phase was separated, washed (saturated aqueous NaHCO₃),dried (Na₂SO₄) and evaporated to give only a small amount of a paleyellow residue. The aqueous phase was subsequently saturated with solidNaCl and the mixture was extracted with DCM (×6). The combined organicextracts were dried (Na₂SO₄) and evaporated to give a white solid. Theaqueous phase was then neutralized with conc. HCl (pH 7) andre-extracted with DCM (×5). The organic extract was again dried (Na₂SO₄)and evaporated to give additional material as an off-white solid. Thesesolids were combined to give4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol (1.145 g,59.2%) as a cream solid which was used as such in the next step withoutfurther purification. LC (Method A): 0.861 min. HRMS(ESI): calcd forC₉H₁₄NO₃S [M+H]⁺ m/z 216.069; found 216.070. ¹H NMR (400 MHz, DMSO-d₆):δ 7.24 (s, 1H), 6.00 (s, 1H), 5.21 (t, J=5.87 Hz, 1H),4.48 (d, J=5.87Hz, 2H), 3.68 (m, 4H), 2.04 (m, 2H), 1.60 (br d, J=13.30 Hz, 2H).

Example 1184-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.040 g, 0.126 mmol) and4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol (0.034 g,0.158 mmol), then the flask was flushed with N₂ and dry THF (2 mL) wasadded. To the resulting suspension was added tri-n-butylphosphine (0.082mL, 0.315 mmol) and then a solution of 1,1′-(azodicarbonyl)dipiperidine(0.080 g, 0.315 mmol) in dry THF (2 mL) was added dropwise (via syringepump) over 30 min. The resulting mixture was stirred at room temperaturefor another 1 h and then it was diluted with EtOAc, washed (saturatedaqueous NaHCO₃, H₂O, brine), dried (Na₂SO₄) and evaporated to give apale yellow gum. Flash chromatography (Isco/0-30% ether-DCM, then 0-100%EtOAc-DCM and finally 0-3% MeOH-DCM) gave4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol(0.049 g, 76%) as a colorless gum which was lyophilized from MeCN-wateras an off-white solid. LC (Method A): 2.106 min. HRMS(ESI): calcd forC₂₃H₂₃N₄O₆S₂ [M+H]⁺ m/z 515.106; found 515.107. ¹H NMR (400 MHz,DMSO-d₆): δ 8.33 (s, 1H), 7.66 (s, 1H), 6.95 (s, 1H), 6.80 (s, 1H), 6.59(d, J=1.57 Hz, 1H), 5.23 (s, 2H), 4.17 (s, 3H), 3.77 (s, 3H), 3.70 (m,4H), 2.08 (ddd, J=5.48, 10.96, 13.30 Hz, 1H), 1.64 (br d, J=12.52 Hz,2H).

Example 1196-(4-((2-(4-Fluorotetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

119A. 4-(4-Methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol

A solution of 4-methylthiazole (0.910 mL, 10.0 mmol) in dry THF (45 mL)was cooled at −78° C. under N₂ and then n-butyllithium (1.45 M inhexanes, 7.59 mL, 11.00 mmol) was added dropwise. The resulting mixturewas stirred for 15 min to give a bright yellow solution. To this mixturewas slowly added a solution of dihydro-2H-pyran-4(3H)-one (1.108 mL,12.00 mmol) in dry THF (5 mL) and the mixture was kept at −78° C. for 1h, to give a pale yellow solution. The reaction was then quenched by theaddition of saturated aqueous NH₄Cl (5 mL) and the mixture waspartitioned with EtOAc-water. The organic phase was separated, washed(brine), dried (Na₂SO₄) and evaporated to give a pale yellow oil whichsolidified on standing in vacuo. Flash chromatography (Isco/0-50%acetone-hexane) afforded4-(4-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol (1.535 g, 77%) as awhite crystalline solid. This material was used as such in the nextstep. LC (Method A): 1.091 min. HRMS: calcd for C₉H₁₄NO₂S [M+1]⁺ m/z200.075; found 200.075. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.59 (br d,J=12.52 Hz, 2H), 2.04 (ddd, J=5.87, 10.56, 13.30 Hz, 2H), 2.29 (s, 3H),3.72-3.62 (m, 4H), 5.95 (s, 1H), 7.08 (s, 1H).

119B. (2-(4-Fluorotetrahydro-2H-pyran-4-yl)-4-methylthiazole

To a solution of 4-(4-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol (0.022g, 0.110 mmol) in dichloromethane (1.75 mL), cooled at 0° C. undernitrogen, was added DAST (0.018 mL, 0.138 mmol) dropwise. The resultingreaction mixture was allowed to stir at 0° C. for 2 h and then saturatedaqueous sodium carbonate was added and the heterogeneous mixture wasstirred vigorously for 15 min to ensure complete quenching. The mixturewas then partitioned with dichloromethane and saturated aqueousbicarbonate solution. The organic layer was separated, dried overmagnesium sulfate and concentrated under reduced pressure. The crudeproduct (0.021 g, 95%) was used as such for the next step. LC (MethodA): 1.722 min. LCMS (APCI): calcd for C₉H₁₃FNOS [M+H]⁺ m/z 202.07, found202.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 2.00-2.11, (m, 2H), 2.28-2.49 (m,2H), 2.45 (s, 3H), 3.79-3.98 (m, 4H), 6.88 (s, 1H).

119C. 4-(Bromomethyl)-2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazole

A sealed tube was charged with2-(4-fluorotetrahydro-2H-pyran-4-yl)-4-methylthiazole (0.021 g, 0.104mmol), carbon tetrachloride (2 mL), NBS (0.0204 g, 0.115 mmol) andbenzoyl peroxide (0.002 g, 8.26 μmol). The reaction mixture was thenstirred at 85° C. for 2.5 h. After cooling, the crude reaction mixturewas taken up in dichloromethane and the solid present was removed byfiltration. The filtrate was concentrated and the crude residue waspurified by preparative HPLC (Method A) to give pure the title compound(0.010 g, 34%). LC (Method A): 1.784 min. LCMS (APCI): calcd forC₉H₁₂BrFNOS [M+H]⁺ m/z 279.98, found 280.0. ¹H NMR (CD₃OD, 400 MHz) δppm: 1.96-2.09 (m, 2H), 2.26-2.46 (m, 2H), 3.77-3.96 (m, 4H), 4.62 (s,2H), 7.60 (s, 1H).

Example 1196-(4-((2-(4-Fluorotetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a solution of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.009 g, 0.028 mmol) and4-(bromomethyl)-2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazole (0.010 g,0.036 mmol), stirred in DMF (1 mL) under a nitrogen atmosphere, wasadded potassium carbonate (0.009 g, 0.065 mmol) and the resultingreaction mixture was stirred at room temperature for 2 h. The crudereaction mixture was diluted with dichloromethane, washed with water andbrine, dried over MgSO₄, filtered and concentrated. The crude residueobtained was purified by preparative HPLC (Method A) to give the puretitle compound (0.010 g, 68%). LC (Method A): 2.376 min. LCMS (ESI):calcd for C₂₃H₂₂FN₄O₅S₂ [M+H]⁺ m/z 517.1016, found 517.1054. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 2.01-2.15 (m, 2H), 2.17-2.39 (m, 2H),3.63-3.77 (m, 2H), 3.78-3.90 (m, 2H), 3.81 (s, 3H), 4.20 (s, 3H), 5.32(s, 2H), 6.62 (d, J=2.0 Hz, 1H), 6.84 (d, J=0.8 Hz, 1H), 7.00 (s, 1H),7.93 (s, 1H), 8.37 (s, 1H).

Example 1202-Methoxy-6-(6-methoxy-4-((2-(4-methoxytetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

120A.4-4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(4-methoxytetrahydro-2H-pyran-4-yl)thiazole

To a suspension of sodium hydride (0.097 g, 2.428 mmol) [Note: 60% NaHin oil was washed free of oil with hexanes (×2) before dry THF was addedto the reaction flask] in dry THF (5 mL) under N₂ was added a solutionof4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol(Example 118A, 0.400 g, 1.214 mmol) in dry THF (3 mL) and the mixturewas stirred at room temperature until there was no more gas evolution(ca. 30 min). To the resulting pale yellow mixture was added iodomethane(0.091 mL, 1.457 mmol) dropwise and stirring was continued at roomtemperature for 16 h. The reaction mixture was then quenched by thecareful addition of saturated aqueous NH₄Cl (5 mL) and was subsequentlypartitioned with EtOAc-water. The organic phase was separated, dried(Na₂SO₄) and evaporated to give a nearly colorless oil. Flashchromatography (Isco/0-50% EtOAc-hexane) afforded4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-methoxytetrahydro-2H-pyran-4-yl)thiazole(0.362 g, 87%) as a colorless oil which was used as such in the nextstep. LC (Method A): 2.442 min. HRMS(ESI): calcd for C₁₆H₃₀NO₃SSi [M+H]⁺m/z 344.171; found 344.173. ¹H NMR (400 MHz, DMSO-d₆): δ 7.42 (s, 1H),4.67 (s, 2H), 3.58 (m, 4H), 2.99 (s, 3H), 2.01 (m, 2H), 1.87 (m, 2H),0.81 (s, 9H), 0.00 (s, 6H).

120B. (2-(4-Methoxytetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

To a solution of4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-methoxytetrahydro-2H-pyran-4-yl)thiazole(0.358 g, 1.042 mmol) in dry THF (10 mL) under N₂ was addedtriethylamine trihydrofluoride (0.848 mL, 5.21 mmol) dropwise and themixture was stirred at room temperature for 5 h. The mixture was thendiluted with DCM and the solution was washed (saturated aqueous NaHCO₃),dried (Na₂SO₄) and evaporated to give(2-(4-methoxytetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (0.227 g,95%) as a nearly colorless gum which was used as such in the next step.LC (Method A): 1.301 min. HRMS(ESI): calcd for C₁₀H₁₆NO₃S [M+H]⁺ m/z230.085; found 230.085. ¹H NMR (400 MHz, DMSO-d₆): δ 7.38 (t, J=1.17 Hz,1H), 5.23 (t, J=5.48 Hz, 1H), 4.48 (dt, J=1.17, 5.48 Hz, 2H), 3.58 (m,4H), 2.99 (s, 3H), 2.01 (m, 2H), 1.87 (m, 2H).

Example 1202-Methoxy-6-(6-methoxy-4-((2-(4-methoxytetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.040 g, 0.126 mmol) and(2-(4-methoxytetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (0.036 g,0.158 mmol), then the flask was flushed with N₂ and dry THF (2 mL) wasadded. To the resulting suspension was added tri-n-butylphosphine (0.082mL, 0.315 mmol) and then a solution of 1,1′-(azodicarbonyl)dipiperidine(0.080 g, 0.315 mmol) in dry THF (2 mL) was added dropwise (via syringepump) over 30 min. The resulting mixture was stirred at room temperaturefor another 1 h and then it was diluted with EtOAc, washed (saturatedaqueous NaHCO₃, H₂O, brine), dried (Na₂SO₄) and evaporated to give apale yellow gum. Flash chromatography (Isco/0-50% ether-DCM) gave2-methoxy-6-(6-methoxy-4-((2-(4-methoxytetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(0.045 g, 67.5%) as a white solid. LC (Method A): 2.348 min. HRMS(ESI):calcd for C₂₄H₂₅N₄O₆S₂ [M+H]⁺ m/z 529.122; found 529.124. ¹H NMR (400MHz, DMSO-d₆): δ 8.33 (s, 1H), 7.84 (s, 1H), 6.95 (s, 1H), 6.80 (s, 1H),6.59 (d, J=1.57 Hz, 1H), 5.23 (s, 2H), 4.17 (s, 3H), 3.77 (s, 3H), 3.64(m, 4H), 3.06 (s, 3H), 2.09 (m, 2H), 1.95 (m, 2H).

Example 1214-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol

121A.4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol

A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 5.00 g, 16.22 mmol) in dry THF (75 mL) was cooled at −78°C. under N₂ and then 1.45 M n-butyllithium (11.89 mL, 17.84 mmol) wasadded dropwise. The resulting mixture was stirred for 15 min to give apale brown solution. To this mixture was slowly added a solution of3,5-dimethyldihydro-2H-pyran-4(3H)-one (2.494 g, 19.46 mmol) [Aube, J.et al., J. Org. Chem., 69:1716 (2004)] in dry THF (5 mL) and stirringwas continued at −78° C. for 2 h to give a light brown solution. Thereaction was then quenched by the addition of saturated aqueous NH₄Cl(10 mL), the cooling bath was removed and the mixture was partitionedwith EtOAc-water. The organic phase was separated, washed (water,brine), dried (Na₂SO₄) and evaporated to give a pale yellow oil. Flashchromatography (Isco/0-100% EtOAc-toluene) gave the impure product as acolorless oil (2.11 g). This material was rechromatographed (Isco/0-50%ether-chloroform) to give4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(1.767 g, 30.5%) as a viscous oil which solidified on standing. Thismaterial was used as such in the next step. LC (Method A): 2.352 min.HRMS(ESI): calcd for C₁₇H₃₂NO₃SSi [M+H]⁺ m/z 358.187; found 358.188. ¹HNMR (400 MHz, DMSO-d₆): δ 7.30 (s, 1H), 5.94 (s, 1H), 4.64 (s, 2H), 3.78(ddq, J=1.57, 6.26, 12.52 Hz, 2H), 1.98 (d, J=12.52 Hz, 2H), 1.36 (t,J=12.52 Hz, 2H), 1.00 (d, J=6.26 Hz, 6H), 0.80 (s, 9H), 0.00 (s, 6H).

121B.4-(4-(Hydroxymethyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol

To a solution of4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(1.742 g, 4.87 mmol) in dry THF (30 mL) under N₂ was added triethylaminetrihydrofluoride (2.380 mL, 14.61 mmol) dropwise and the mixture wasstirred at room temperature for 14 h. The mixture was then diluted withDCM and the solution was washed (saturated aqueous NaHCO₃), dried(Na₂SO₄) and evaporated to give the product (0.800 g, 68%) as a paleyellow solid. The aqueous phase was saturated with solid NaCl andextracted with EtOAc (×2) to give (after separation, drying andevaporation of the combined organic phase) an additional 0.329 g (28%)of the product as a white crystalline solid. The solids were combined togive4-(4-(hydroxymethyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(1.129 g, 95%) which was essentially pure and was used as such in thenext step. LC (Method A): 1.210 min. HRMS(ESI): calcd for C₁₁H₁₈NO₃S[M+H]⁺ m/z 244.100; found 244.101. ¹H NMR (400 MHz, DMSO-d₆): δ 7.29 (s,1H), 5.95 (s, 1H), 5.20 (t, J=5.87 Hz, 1H), 4.48 (d, J=5.48 Hz, 2H),3.78 (ddq, J=1.96, 6.26, 11.35 Hz, 2H), 2.02 (d, J=12.91 Hz, 2H), 1.39(t, J=11.74 Hz, 2H), 1.04 (d, J=6.26 Hz, 6H).

Example 1214-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.600 g, 1.891 mmol) and4-(4-(hydroxymethyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(0.552 g, 2.269 mmol), then the flask was flushed with N₂ and dry THF(20 mL) was added. To the resulting suspension was addedtri-n-butylphosphine (1.228 mL, 4.73 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (1.205 g, 4.73 mmol) in dry THF (8 mL)was added dropwise (via syringe pump) over 30 min. The resulting mixturewas stirred at room temperature for another 1 h and then it was quenchedwith saturated aqueous NaHCO₃ and partitioned with DCM-water. Theorganic extract was separated, dried (Na₂SO₄) and evaporated to give apale yellow solid. Flash chromatography (Isco/0-100% EtOAc-DCM) gave asolid which was triturated with MeCN to give (after filtration, washingwith a minimum volume of MeCN and drying in vacuo)4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(679 mg, 66%) as a cream solid. LC (Method A): 2.202 min. HRMS(ESI):calcd for C₂₅H₂₇N₄O₆S₂ [M+H]⁺ m/z 543.137; found 543.140. ¹H NMR (400MHz, DMSO-d₆): δ 8.30 (s, 1H), 7.68 (s, 1H), 6.89 (s, 1H), 6.76 (s, 1H),6.59 (d, J=1.96 Hz, 1H), 6.01 (s, 1H), 5.22 (s, 2H), 4.14 (s, 3H), 3.76(m, 2H), 3.73 (s, 3H), 2.00 (d, J=11.76 Hz, 2H), 1.37 (t, J=11.74 Hz,2H), 0.99 (d, J=6.26 Hz, 6H).

Example 1226-(4-((2-(4-Fluoro-2,6-dimethyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxy-imidazo[2,1-b][1,3,4]thiadiazole

To an ice-cold suspension of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(0.023 g, 0.042 mmol) in DCM (3 mL) under N₂ was added DAST (0.014 mL,0.106 mmol) dropwise and the resulting mixture was stirred at 0° C. for20 min. Another aliquot of DAST (0.007 mL, 0.053 mmol) was added, thecooling bath was removed and the resulting pale yellow solution wasstirred at room temperature for 16h. The reaction mixture was thenre-cooled at 0° C. and quenched by the dropwise addition of saturatedaqueous NaHCO₃ (3 mL). The mixture was vigorously stirred at 0° C. for 5min and then the cooling bath was removed and stirring was continueduntil no more gas evolution was observed. The organic phase wassubsequently separated and applied directly to a silica gel pre-column.Flash chromatography (Isco/0-100% EtOAc-hexane) afforded6-(4-((2-(4-fluoro-2,6-dimethyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxy-imidazo[2,1-b][1,3,4]thiadiazole(0.020 g, 87% yield) as a colorless gum which was lyophilized fromMeCN-water to give a white solid. NMR indicated that this was a 3:2mixture of isomers. LC (Method A): 2.470 min. HRMS(ESI): calcd forC₂₅H₂₆FN₄O₅S₂ [M+H]⁺ m/z 545.133; found 545.135. ¹H NMR (400 MHz,DMSO-d₆): δ 8.31 (s, 0.4H), 8.30 (s, 0.6H), 7.97 (s, 0.6H), 7.84 (s,0.4H), 6.93 (s, 0.4H), 6.91 (s, 0.6H), 6.77 (m, 1H), 6.58 (d, J=1.96 Hz,0.6H), 6.56 (d, J=1.57 Hz, 0.4H), 5.29 (s, 1.2H), 5.23 (s, 0.8H), 4.14(s, 3H), 3.76 (m, 0.8H), 3.74 (s, 1.2H), 3.73 (s, 1.8H), 3.53 (m, 1.2H),2.38 (dd, J=1.96, 12.52 Hz, 1H), 2.07 (m, 1H), 1.83-1.61 (m, 2H), 1.10(d, J=6.26 Hz, 2.4H), 1.08 (d, J=6.26 Hz, 3.6H).

Example 1233-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo-furan-4-yl)oxy)methyl)thiazol-2-yl)tetrahydrofuran-3-ol

123A.3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydrofuran-3-ol

A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 1.542 g, 5.000 mmol) in dry THF (20 mL) was cooled at −78°C. under N₂ and then 1.45 M n-butyllithium (3.79 mL, 5.50 mmol) wasadded dropwise. The resulting mixture was stirred for 15 min to give apale yellow-brown solution. To this mixture was slowly added a solutionof dihydrofuran-3(2H)-one (0.517 g, 6.00 mmol) in dry THF (2.5 mL) andthe mixture was stirred at −78° C. for 1 h, to give a light brownsolution. The reaction was then quenched by the addition of saturatedaqueous NH₄Cl (5 mL), the cooling bath was removed and the mixture waspartitioned with EtOAc-water. The organic phase was separated, washed(brine), dried (Na₂SO₄) and evaporated to give a pale yellow oil. Flashchromatography (Isco/0-50% EtOAC-hexane) afforded3-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydrofuran-3-ol(1.052 g, 66.7%) as an oil which crystallized on standing in vacuo. Thismaterial was used as such in the next step. LC (Method A): 2.226 min.HRMS(ESI): calcd for C₁₄H₂₆NO₃SSi [M+H]⁺ m/z 316.140; found 316.147. ¹HNMR (400 MHz, DMSO-d₆): δ 7.28 (s, 1H), 6.32 (s, 1H), 4.65 (s, 2H), 3.92(m, 2H), 3.78 (q, J=9.00 Hz, 2H), 2.36 (dt, J=9.00, 12.52 Hz, 1H), 2.09(dt, J=5.09, 12.52 Hz, 1H), 0.82 (s, 9H), 0.00 (s, 6H).

123B. 3-(4-(Hydroxymethyl)thiazol-2-yl)tetrahydrofuran-3-ol

To a solution of3-(4-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydrofuran-3-ol(1.022 g, 3.24 mmol) in dry THF (20 mL) under N₂ was added triethylaminetrihydrofluoride (1.319 mL, 8.10 mmol) dropwise and the mixture wasstirred at room temperature for 16 h. The mixture was then diluted withDCM and then saturated aqueous NaHCO₃ was added (Caution: vigorous gasevolution.). The organic phase was separated, washed (saturated aqueousNaHCO₃), dried (Na₂SO₄) and evaporated to give a colorless gum whichsolidified on standing in vacuo. The aqueous phase was saturated withsolid NaCl and back-extracted with DCM to give (after drying as before)additional colorless gum which also solidified on standing. These solidswere combined to give3-(4-(hydroxymethyl)thiazol-2-yl)tetrahydrofuran-3-ol as a cream solid.This material was used as such in the next step without furtherpurification. LC (Method A): 0.734 min. HRMS(ESI): calcd for C₉H₁₂NO₃S[M+H]⁺ m/z 202.054; found 202.055. ¹H NMR (400 MHz, DMSO-d₆): δ 7.18 (s,1H), 6.23 (s, 1H), 5.12 (br s, 1H), 4.37 (s, 2H), 3.85 (dd, J=1.57, 9.00Hz, 1H), 3.84 (d, J=9.00 Hz, 1H), 3.74 (d, J=9.00 Hz, 1H), 3.68 (d,J=9.00 Hz, 1H), 2.29 (dt, J=9.00, 12.91 Hz, 1H), 2.02 (dt, J=5.09, 12.52Hz, 1H).

Example 1233-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydrofuran-3-ol

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.063 g, 0.200 mmol) and3-(4-(hydroxymethyl)thiazol-2-yl)tetrahydrofuran-3-ol (0.040 g, 0.200mmol), then the flask was flushed with N₂ and dry THF (5 mL) was added.To the resulting suspension was added tri-n-butylphosphine (0.123 mL,0.500 mmol) and then a solution of 1,1′-(azodicarbonyl)dipiperidine(0.127 g, 0.500 mmol) in dry THF (2 mL) was added dropwise (via syringepump) over 30 min. The resulting mixture was stirred at room temperaturefor another 1 h and then it was diluted with EtOAc, washed (saturatedaqueous NaHCO₃, H₂O, brine), dried (Na₂SO₄) and evaporated to give apale yellow semi-solid. Flash chromatography (Isco/0-100% EtOAc-DCM)gave3-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydrofuran-3-ol(0.015 g, 14.98%) as a solid. LC (Method A): 2.161 min. HRMS(ESI): calcdfor C₂₂H₂₁N₄O₆S₂ [M+H]⁺ m/z 501.090; found 501.092. ¹H NMR (400 MHz,DMSO-d₆): δ 8.33 (s, 1H), 7.71 (s, 1H), 6.95 (s, 1H), 6.80 (s, 1H), 6.58(d, J=1.57 Hz, 1H), 6.44 (s, 1H), 5.23 (s, 2H), 4.17 (s, 3H), 3.98 (d,J=5.09 Hz, 1H), 3.96 (d, J=5.48 Hz, 1H), 3.88 (d, J=9.00 Hz, 1H), 3.83(d, J=9.00 Hz, 1H), 3.77 (s, 3H), 2.43 (m, 1H), 2.16 (dt, J=5.09, 12.52Hz, 2H).

Example 1244-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol

124A. (5-Methylthiazol-4-yl)methanol

To an ice-cold solution of ethyl 5-methylthiazole-4-carboxylate (2.57 g,15.00 mmol) in dry THF (50 mL) under N₂ was added lithium borohydride(0.654 g, 30.0 mmol) all at once, followed by MeOH (1.214 mL, 30.0 mmol)dropwise. The cooling bath was then removed and the mixture was stirredat room temperature for 16 h. The mixture was then re-cooled at 0° C.and cautiously quenched by the slow addition of saturated aqueous NH₄Cl(20 mL) with vigorous stirring. The cooling bath was then removed andthe mixture was partitioned with EtOAc-water. The organic phase wasseparated and then it was washed with water and brine. The combinedaqueous phase was saturated with solid NaCl and back-extracted withEtOAc (×4). The combined organic phase was dried (Na₂SO₄) and evaporatedto give a yellow oil which was purified by flash chromatography(Isco/0-100% EtOAc-DCM) to give (5-methylthiazol-4-yl)methanol (1.144 g,59.0%) as a nearly colorless oil which crystallized on standing in vacuoto give a solid. This material was used as such in the next step. LC(Method X): 0.620 min. HRMS(ESI): calcd for C₅H₈NOS [M+H]⁺ m/z 130.032;found 130.032. ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H), 4.98 (br s,1H), 4.46 (s, 2H), 2.40 (s, 3H).

124B. 4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylthiazole

To a solution of (5-methylthiazol-4-yl)methanol (1.134 g, 8.78 mmol) andimidazole (1.793 g, 26.3 mmol) in DMF (40 mL) under N₂ was addedtert-butyldimethylchlorosilane (1.455 g, 9.66 mmol) and the resultingmixture was stirred at room temperature under N₂ for 16 h. The solutionwas then concentrated under reduced pressure and the residual oil waspartitioned with EtOAc-saturated aqueous NH₄Cl. The organic phase wasseparated, washed (water, brine), dried (Na₂SO₄) and evaporated to givea pale yellow, viscous oil. Flash chromatography (Isco/0-10% EtOAc-DCM)afforded 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole(1.484 g, 69.4%) as a colorless oil which was used as such in the nextstep. LC (Method A): 2.272 min. HRMS(ESI): calcd for C₁₁H₂₂NOSSi [M+H]⁺m/z 244.119; found 244.123. ¹H NMR (400 MHz, CDCl₃): δ 8.46 (s, 1H),4.74 (s, 2H), 2.43 (s, 3H), 0.82 (s, 9H), 0.00 (s, 6H).

124C.4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol

A solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole(1.480 g, 6.08 mmol) in dry THF (45 mL) was cooled at −78° C. under N₂and then n-butyllithium (1.45 M in hexanes, 5.03 mL, 7.30 mmol) wasadded dropwise. The initially colorless solution became bright purplenear the end of the addition and the resulting mixture was stirred for15 min at the same temperature. To this purple solution was slowly addeda solution of dihydro-2H-pyran-4(3H)-one (0.674 mL, 7.30 mmol) in dryTHF (3 mL) and the solution was kept at −78° C. for 1 h, to give a paleorange solution. The reaction was then quenched by the addition ofsaturated aqueous NH₄Cl (10 mL) and then the cooling bath was removedand the mixture was partitioned with EtOAc-water. The organic phase wasseparated, washed (brine), dried (Na₂SO₄) and evaporated to give a paleyellow oil. Flash chromatography (Isco/0-30% acetone-hexane) afforded4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol(1.865 g, 89%) as a colorless oil which was used as such in the nextstep. LC (Method A): 2.297 min. HRMS(ESI): calcd for C₁₆H₃₀NO₃SSi [M+H]⁺m/z 344.172; found 344.176. ¹H NMR (400 MHz, DMSO-d₆): δ 5.92 (s, 1H),4.59 (s, 2H), 3.66 (m, 4H), 2.34 (s, 3H), 2.00 (m, 2H), 1.57 (d, J=12.91Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H).

124D. 4-(4-(Hydroxymethyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol

To a solution of4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol(1.861 g, 5.42 mmol) in dry THF (15 mL) under N₂ was added triethylaminetrihydrofluoride (2.65 mL, 16.25 mmol) dropwise and the mixture wasstirred at room temperature for 18 h. The mixture was then concentratedto about one-half volume under reduced pressure and the concentrate wasdiluted with DCM and the solution was washed (saturated aqueous NaHCO₃),dried (Na₂SO₄) and evaporated to give4-(4-(hydroxymethyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol(1.114 g, 90%) as a white solid. This material was essentially pure andwas used as such in the next step. LC (Method A): 1.062 min. HRMS(ESI):calcd for C₁₀H₁₆NO₃S [M+H]⁺ m/z 230.085; found 230.086. ¹H NMR (400 MHz,DMSO-d₆): δ 5.90 (s, 1H), 4.93 (t, J=5.87 Hz, 1H), 4.38 (d, J=5.48 Hz,2H), 3.67 (m, 4H), 2.34 (s, 3H), 2.02 (m, 2H), 1.58 (d, J=11.74 Hz, 2H).

Example 1244-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.060 g, 0.189 mmol) and4-(4-(hydroxymethyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol(0.054 g, 0.236 mmol), then the flask was flushed with N₂ and dry THF (3mL) was added. To the resulting suspension was addedtri-n-butylphosphine (0.123 mL, 0.473 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (0.120 g, 0.473 mmol) in dry THF (2 mL)was added dropwise (via syringe pump) over 30 min. The resulting mixturewas stirred at room temperature for another 1 h and then it was dilutedwith EtOAc, washed (saturated aqueous NaHCO₃, H₂O, brine), dried(Na₂SO₄) and evaporated to give a pale yellow semi-solid. Flashchromatography (Isco/0-100% EtOAc-DCM) gave4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol(0.077 g, 77%) as a white solid. LC (Method A): 2.214 min. HRMS(ESI):calcd for C₂₄H₂₅N₄O₆S₂ [M+H]⁺ m/z 529.122; found 529.125. ¹H NMR (400MHz, DMSO-d₆): δ 8.30 (s, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 6.59 (d,J=1.57 Hz, 1H), 5.98 (s, 1H), 5.13 (s, 2H), 4.13 (s, 3H), 3.74 (s, 3H),3.65 (m, 4H), 2.39 (s, 3H), 2.02 (m, 2H), 1.58 (d, J=12.91 Hz, 2H).

Example 1256-(4-((2-(4-Fluorotetrahydro-2H-pyran-4-yl)-5-methylthiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]-thiadiazole

To an ice-cold suspension of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol(0.025 g, 0.047 mmol) in DCM (3 mL) under N₂ was added DAST (0.016 mL,0.118 mmol) dropwise and the resulting mixture was stirred at 0° C. for20 min. The cooling bath was then removed and the resulting pale yellowsolution was stirred at room temperature for 1 h. The reaction mixturewas then re-cooled at 0° C. and quenched by the dropwise addition ofsaturated aqueous NaHCO₃ (3 mL). The mixture was vigorously stirred at0° C. for 5 min and then the cooling bath was removed, the mixture wasdiluted with DCM and additional saturated aqueous NaHCO₃ and stirringwas continued until no more gas evolution was observed. The organicphase was then separated and applied directly to a silica gelpre-column. Flash chromatography (Isco/0-100% EtOAc-hexane) afforded6-(4-((2-(4-fluorotetrahydro-2H-pyran-4-yl)-5-methylthiazol-4-yl)methoxy)-6-methoxybenzo-furan-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.020 g, 80%) as a colorless gum which was lyophilized from MeCN-waterto give a white solid. LC (Method A): 2.405 min. HRMS(ESI): calcd forC₂₄H₂₄FN₄O₅S₂ [M+H]⁺ m/z 531.117; found 531.118. ¹H NMR (400 MHz,DMSO-d₆): δ 8.30 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.58 (d, J=1.96Hz, 1H), 5.18 (s, 2H), 4.13 (s, 3H), 3.74 (s, 3H), 3.74 (m, 2H), 3.62(dt, J=1.96, 10.96 Hz, 2H), 2.45 (s, 3H), 2.23-2.10 (m, 2H), 1.99 (m,2H).

Examples 126 and 1278-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol,and6-(4-((2-(1,4-Dioxaspiro-[4.5]dec-7-en-8-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole,respectively

126A.8-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-1,4-dioxaspiro-[4.5]decan-8-ol

A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 1.00 g, 3.24 mmol) in dry THF (15 mL) was cooled at −78°C. under N₂ and then n-butyllithium (1.45 M in hexanes, 2.68 mL, 3.89mmol) was added dropwise. The resulting mixture was stirred for 30 minto give a light yellow-brown solution. To this mixture was addeddropwise a solution of 1,4-dioxaspiro[4.5]decan-8-one (0.608 g, 3.89mmol) in dry THF (4 mL) and the mixture was kept at −78° C. for 2 h. Thereaction was then quenched by the addition of saturated aqueous NH₄Cl (5mL), then the cooling bath was removed and the mixture was partitionedwith EtOAc-water. The organic phase was separated, washed (brine), dried(Na₂SO₄) and evaporated to give a light yellow oil which was purified byflash chromatography (Isco/0-100% EtOAc-hexane) to give8-(4-(((tert-butyldimethylsilyl)oxy)-methyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol(0.920 g, 73.6%) as a colorless gum which crystallized on standing invacuo. This material was used as such in the next step. LC (Method A):2.287 min. HRMS(ESI): calcd for C₁₈H₃₂NO₄SSi [M+H]⁺ m/z 386.182; found386.182. ¹H NMR (400 MHz, DMSO-d₆): δ 7.20 (s, 1H), 5.85 (s, 1H), 4.64(s, 2H), 3.81 (s, 4H), 2.03 (dt, J=3.91, 12.91 Hz, 2H), 1.78 (dt,J=4.30, 13.30 Hz, 2H), 1.68 (d, J=12.91 Hz, 2H), 1.53 (d, J=12.52 Hz,2H), 0.82 (s, 9H), 0.00 (s, 6H).

126B. 8-(4-(Hydroxymethyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of8-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol(0.916 g, 2.376 mmol) in dry THF (10 mL) under N₂ was addedtriethylamine trihydrofluoride (1.160 mL, 7.13 mmol) dropwise and themixture was stirred at room temperature for 18 h. The mixture was thenpartitioned with EtOAc-saturated aqueous NaHCO₃ and the organic phasewas washed (brine), dried (Na₂SO₄) and evaporated to give8-(4-(hydroxymethyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (0.579g, 90%) as a colorless gum which crystallized on standing in vacuo. Thismaterial was essentially pure and was used as such in the next step. LC(Method A): 1.148 min. HRMS(ESI): calcd for C₁₂H₁₈NO₄S [M+H]⁺ m/z272.096; found 272.095. ¹H NMR (400 MHz, DMSO-d₆): δ 7.20 (s, 1H), 5.86(s, 1H), 5.20 (t, J=5.48 Hz, 1H), 4.46 (d, J=5.09 Hz, 2H), 3.84 (s, 4H),2.07 (dt, J=3.91, 12.91 Hz, 2H), 1.81 (dt, J=4.30, 13.30 Hz, 2H), 1.70(d, J=12.91 Hz, 2H), 1.55 (d, J=12.52 Hz, 2H).

Examples 126 and 1278-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-oland6-(4-((2-(1,4-dioxaspiro-[4.5]dec-7-en-8-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.600 g, 1.891 mmol) and8-(4-(hydroxymethyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (0.539g, 1.985 mmol), then the flask was flushed with N₂ and dry THF (15 mL)was added. To the resulting suspension was added tri-n-butylphosphine(1.228 mL, 4.73 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (1.205 g, 4.73 mmol) in dry THF (10 mL)was added over ca. 30 min (via syringe pump). The resulting mixture wasstirred at room temperature for another 1 h and then it was diluted withEtOAc, washed (saturated aqueous NaHCO₃, H₂O, brine), dried (Na₂SO₄) andevaporated to give a light amber semi-solid. Flash chromatography(Isco/0-100% EtOAc-DCM) afforded 2 major products. Fraction 1 wasidentified as6-(4-((2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.127 g, 12.15%) and was isolated as a white foam. This material waslyophilized from MeCN-water to give a cream solid. LC (Method A): 2.362min. HRMS(ESI): calcd for C₂₆H₂₅N₄O₆S₂ [M+H]⁺ m/z 553.121; found553.122. ¹H NMR (400 MHz, DMSO-d₆): δ 8.34 (s, 1H), 7.67 (s, 1H), 6.97(s, 1H), 6.80 (s, 1H), 6.57 (s, 1H), 6.50 (br s, 1H), 5.24 (s, 2H), 4.17(s, 3H), 3.89 (s, 4H), 3.77 (s, 3H), 2.63 (br s, 2H), 2.38 (br s, 2H),1.79 (t, J=6.26 Hz, 2H). Fraction 2 was identified as8-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-1,4-dioxaspiro-[4.5]decan-8-ol(0.254 g, 23.54%) and was isolated as an off-white foam. This materialwas lyophilized from MeCN-water to give a cream solid. LC (Method A):2.193 min. HRMS(ESI): calcd for C₂₆H₂₇N₄O₇S₂ [M+H]⁺ m/z 571.132; found571.132. ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (s, 1H), 7.58 (s, 1H), 6.89(s, 1H), 6.75 (s, 1H), 6.53 (s, 1H), 5.92 (s, 1H), 5.16 (s, 2H), 4.12(s, 3H), 3.80 (s, 4H), 3.73 (s, 3H), 2.06 (dt, J=3.13, 12.91 Hz, 2H),1.78 (dt, J=3.52, 13.30 Hz, 2H), 1.70 (d, J=13.30 Hz, 2H), 1.53 (d,J=12.52 Hz, 2H).

Example 1284-Hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexan-one

To a mixture of8-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol(0.013 g, 0.023 mmol) in DCM (1 mL) was added TFA (0.2 mL) and theresulting solution was stirred at room temperature in a sealed flask for18 h. The volatiles were then evaporated to give the impure product as asolid. Flash chromatography (Isco/0-100% EtOAc-DCM) afforded4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)-methyl)thiazol-2-yl)cyclohexanone(0.009 g, 75%) as a white solid. LC (Method A): 2.208 min. HRMS(ESI):calcd for C₂₄H₂₃N₄O₆S₂ [M+H]⁺ m/z 527.105; found 527.106. ¹H NMR (400MHz, DMSO-d₆): δ 8.30 (s, 1H), 7.66 (s, 1H), 6.91 (s, 1H), 6.76 (s, 1H),6.54 (d, J=1.57 Hz, 1H), 6.39 (s, 1H), 5.19 (s, 2H), 4.14 (s, 3H), 3.73(s, 3H), 2.60 (m, 2H), 2.25 (dt, J=4.70, 14.09 Hz, 2H), 2.18 (m, 2H),2.06 (m, 2H).

Example 129 tert-Butyl4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidine-1-carboxylate

129A. tert-Butyl4-((((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4-hydroxypiperidine-1-carboxylate

A solution of 4-((((tert-butyldimethylsilyl)oxy)methyl)thiazole (0.738g, 3.22 mmol) in dry THF (8 mL) was cooled at −78° C. under N₂ and thenn-butyllithium (1.45 M in hexanes, 2.440 mL, 3.54 mmol) was addeddropwise. The resulting mixture was stirred for 35 min to give a palebrown solution. To this mixture was slowly added a solution oftert-butyl 4-oxopiperidine-1-carboxylate (0.769 g, 3.86 mmol) in dry THF(2 mL) and the mixture was stirred at −78° C. for 2 h to give a lightbrown solution. The reaction was then quenched by the addition ofsaturated aqueous NH₄Cl (5 mL), the cooling bath was removed and themixture was partitioned with EtOAc-water. The organic phase wasseparated, washed with brine, dried (MgSO₄) and evaporated to give ayellow oil. This oil was purified by flash chromatography usinghexanes-EtOAc as eluent to give tert-butyl4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4-hydroxypiperidine-1-carboxylate(0.850 g, 61.6%) as a clear, colorless gum: LC (Method A): 2.427 min.LCMS (APCI): calcd for C₂₀H₃₇N₂O₄SSi [M+H]⁺ m/z 429.22, found 429.20.

129B. tert-Butyl4-hydroxy-4-(4-(hydroxymethyl)thiazol-2-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4-hydroxypiperidine-1-carboxylate(0.850 g, 1.983 mmol) in THF (11 mL) was added triethylaminetrihydrofluoride (1.60 mL, 9.83 mmol) and the reaction mixture wasstirred at room temperature for 4 h. The resulting mixture was thenpartitioned with EtOAc-saturated aqueous NaHCO₃ and the organic phasewas separated, dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by flash chromatography using DCM-EtOAc as eluentto give tert-butyl4-hydroxy-4-(4-(hydroxymethyl)thiazol-2-yl)piperidine-1-carboxylate(0.476 g, 77%) as a clear, colorless oil. LC (Method A): 1.670 min. ¹HNMR (DMSO-d₆, 400 MHz) δ ppm: 7.27 (m, 1H), 6.09 (s, 1H), 5.23 (t, J=5.7Hz, 1H), 4.50 (d, J=4.7 Hz, 2H), 6.82 (d, J=11.3 Hz, 2H), 3.12 (br s,1H), 1.90 (m, 2H), 1.68 (d, J=12.9 Hz, 2H), 1.41 (s, 9H).

Example 129 tert-Butyl4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidine-1-carboxylate

To a suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.202 g, 0.636 mmol) and tert-butyl4-hydroxy-4-(4-(hydroxymethyl)thiazol-2-yl)piperidine-1-carboxylate(0.200 g, 0.636 mmol) in dry THF (8 mL) was added tri-n-butylphosphine(0.413 mL, 1.590 mmol), followed by a solution of ADDP (0.401 g, 1.590mmol) in THF (2 mL) added dropwise over 30 min via syringe pump. Afterstirring for another 30 min, the reaction mixture was partitionedbetween EtOAc and saturated aqueous NaHCO₃. The organic phase wasseparated, washed with brine, dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by flash chromatography usingDCM-EtOAc as eluent to give the title compound (0.263 g, 0.429 mmol,67.4%) as a white solid. LC (Method A): 2.387 min. HRMS(ESI): calcd forC₂₈H₃₂N₅O₇S₂ [M+H]⁺ m/z 614.1743, found 614.1755. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 8.37 (s, 1H), 7.70 (s, 1H), 6.97 (d, J=0.8 Hz, 1H), 6.83(dd, J=0.8, 1.6 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 6.19 (br s, 1H), 5.25(s, 2H), 4.20 (s, 3H), 3.84 (m, 2H), 3.80 (s, 3H), 3.14 (br s, 1H), 1.94(m, 2H), 1.72 (d, J=12.9 Hz, 2H), 1.41 (s, 9H).

Example 130(4-Hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidin-1-yl)(phenyl)methanone

To a stirred suspension of tert-butyl4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidine-1-carboxylate(0.662 g, 1.079 mmol) in DCM (10 mL) was added TFA (3 mL) and theresulting solution was stirred for 4 h at room temperature, before beingconcentrated to dryness to give an amber colored oil. This crude oil waspartitioned with EtOAc-saturated aqueous NaHCO₃ and the organic phasewas separated, dried (MgSO₄), filtered and concentrated to dryness to4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidin-4-ol2,2,2-trifluoroacetate (0.554 g, 1.079 mmol, 100%) as a beige solid. LC(Method A): 1.980 min. HRMS(ESI): calcd for C₂₃H₂₄N₅O₅S₂ [M+H]⁺ m/z514.1219, found 514.1228. To a stirred solution of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)piperidin-4-ol(0.031 g, 0.050 mmol) in DMF (1 mL) was added DIEA (0.070 mL, 0.400mmol) and benzoic acid (0.0073 g, 0.060 mmol), followed by HATU (0.023g, 0.060 mmol). The reaction mixture was stirred for 1 h and then it wasdiluted with DMF (1 mL) and purified by preparative HPLC (Method A).Fractions containing the desired product were concentrated to drynessand the residue was lyophilized from MeCN-water to give the titlecompound (0.022 g, 71.2%) as an amorphous white solid. LC (Method A):2.257 min. HRMS(ESI): calcd for C₃₀H₂₈N₅O₆S₂ [M+H]⁺ m/z 618.1481, found618.1484. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.71 (s, 1H),7.46-7.40 (m, 5H), 6.98 (d, J=0.8 Hz, 1H), 6.84 (dd, J=0.8, 1.6 Hz, 1H),6.63 (d, J=1.6 Hz, 1H), 6.30 (br s, 1H), 5.26 (s, 2H), 4.36 (br s, 1H),4.20 (s, 3H), 3.80 (s, 3H), 3.48 (m, 2H), 3.24 (br s, 1H), 2.03 (br s,2H), 1.79 (m, 2H).

Example 1314-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)-oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

131A. Ethyl 5-iodothiazole-4-carboxylate

To a solution of ethyl 2-aminothiazole-4-carboxylate (2.92 g, 16.96mmol) in dichloromethane (100 mL) was added NIS (5.00 g, 22.22 mmol).The resulting reaction mixture was stirred at room temperature for 24 hand then it was diluted with ethyl acetate, washed with water and brine,dried over MgSO₄, filtered and concentrated to give ethyl2-amino-5-iodothiazole-4-carboxylate (4.75 g, 90%) that was used as suchfor the next step. LC (Method A): 1.549 min. LCMS (APCI): calcd forC₆H₈₁N₂O₂S [M+H]⁺ m/z 298.94, found 299.0.

A solution of ethyl 2-amino-5-iodothiazole-4-carboxylate (4.75 g, 15.93mmol) in DMF (70 mL) was cooled in an ice bath under nitrogen and thentert-butylnitrite (2.74 mL, 23.04 mmol) was added and the mixture wasstirred at room temperature for 2 h. The reaction mixture was pouredinto brine, and the mixture was extracted 3 times with ethyl acetate.The combined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated. The crude residue obtained was purified bycolumn chromatography (Isco, 8 g cartridge) eluting with a gradient ofethyl acetate in hexanes (from 0 to 50%) to give the pure title compound(0.825 g, 18%). LC (Method A): 1.601 min. LCMS (APCI): calcd forC₆H₇₁NO₂S [M+H]⁺ m/z 283.92, found 283.9. ¹H NMR (CDCl₃, 400 MHz) δ ppm:1.45 (t, J=7.0 Hz, 3H), 4.46 (q, J=7.0 Hz, 2H), 8.95 (s, 1H).

131B. Ethyl 5-(trifluoromethyl)thiazole-4-carboxylate

To a sealable tube charged with ethyl 5-iodothiazole-4-carboxylate(0.825 g, 2.91 mmol) and dry DMF (20 mL) was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate (0.742 mL, 5.83 mmol), followedby copper (I) iodide (1.110 g, 5.83 mmol). The reaction vessel wassealed and the reaction mixture was stirred overnight at 85° C. (bathtemperature). The cooled reaction mixture was taken up in ether andfiltered through a pad of CELITE®. The filtrate was then washed withwater and brine, dried over MgSO₄, filtered and concentrated. The cruderesidue obtained was purified by column chromatography (Isco, 24 gcartridge) eluting with a gradient of EtOAc in hexanes (from 0 to 50%)to give the desired compound as a yellow solid (0.438 g, 67%). LC(Method A): 1.750 min. LCMS (APCI): calcd for C₇H₇F₃NO₂S [M+H]⁺ m/z226.01, found 226.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (t, J=7.4 Hz,3H), 4.48 (q, J=7.4 Hz, 2H), 8.90 (s, 1H).

131C. (5-(Trifluoromethyl)thiazol-4-yl)methanol

To an ice-cold solution of ethyl5-(trifluoromethyl)thiazole-4-carboxylate (0.425 g, 1.887 mmol) in dryTHF (50 mL) under nitrogen was added lithium borohydride (0.082 g, 3.77mmol) all at once, followed by dropwise addition of methanol (0.153 mL,3.77 mmol). The cooling bath was then removed and the mixture wasstirred at room temperature for 1 h. The mixture was recooled at 0° C.and cautiously quenched by the slow addition of saturated aqueous NH₄Cl(10 mL) with vigorous stirring. The cooling bath was then removed andthe mixture was partitioned with ethyl acetate-water. The organic phasewas separated, washed with brine, dried over MgSO₄, filtered andconcentrated. The crude residue obtained was purified by columnchromatography (Isco, 12 g cartridge) eluting with a gradient of EtOAcin hexanes (from 0 to 100%) to give the desired product as a pale yellowoil (0.200 g, 58%). LC retention time (Method A): 1.248 min. LCMS(APCI): calcd for C₅H₅F₃NOS [M+H]⁺ m/z 184.00, found 184.0. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 4.90 (s, 2H), 8.96 (s, 1H).

131D.4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(trifluoromethyl)thiazole

To a solution of (5-(trifluoromethyl)thiazol-4-yl)methanol (0.200 g,1.092 mmol) in dichloromethane (10 mL) at room temperature was addedimidazole (0.112 g, 1.638 mmol), followed bytert-butylchlorodimethylsilane (0.206 g, 1.365 mmol). The resultingreaction mixture was stirred at room temperature for 1 h and then thereaction was quenched with MeOH and concentrated under reduced pressure.The crude residue was purified by column chromatography (Isco, 12 gcartridge), eluting with a gradient of ethyl acetate in hexanes (from 0to 50%) to give the desired product as a colorless oil (0.145 g, 45%).LC (Method A): 2.409 min. LCMS (APCI): calcd for C₁₁H₁₉F₃NOSSi [M+H]⁺m/z 298.09, found 298.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 0.11 (s, 6H),0.91 (s, 9H), 4.92 (s, 2H), 8.84 (s, 1H).

131E.4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

A solution of4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(trifluoromethyl)thiazole(0.145 g, 0.488 mmol) in dry THF (5 mL) was cooled at −78° C. undernitrogen before n-butyllithium (1.5 M in hexanes, 0.390 mL, 0.585 mmol)was added dropwise. The solution obtained was stirred for 15 min at −78°C. before a solution of dihydro-2H-pyran-4(3H)-one (0.054 mL, 0.585mmol) in dry THF (1 mL) was slowly added. The resulting reaction mixturewas stirred at −78° C. for 1 h and then it was quenched by the additionof saturated aqueous NH₄Cl (1.5 mL). The cooling bath was then removedand the mixture was diluted with ethyl acetate. The organic phase wasseparated, washed (brine), dried (MgSO₄), filtered and evaporated togive a pale yellow oil. The crude residue obtained was purified bycolumn chromatography (Isco, 12 g cartridge) eluting with a gradient ofEtOAc in hexanes (from 0 to 50%) to give the desired compound as a paleyellow oil (0.185 g, 95%). LC (Method A): 2.415 min. LCMS (APCI): calcdfor C₁₆H₂₇F₃NO₃SSi [M+H]⁺ m/z 398.14, found 398.2. ¹H NMR (CDCl₃, 400MHz) δ ppm: 0.10 (s, 6H), 0.91 (s, 9H), 1.61 (br s, 1H), 1.75-1.82 (m,2H), 2.25-2.36 (m, 2H), 3.83-3.97 (m, 4H), 4.84 (d, J=0.8 Hz, 2H).

131F.4-(4-(Hydroxymethyl)-5-(trifluoromethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

To a solution of4-(4-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol(0.185 g, 0.465 mmol) in THF (3 mL) at room temperature was added TBAF(75% solution in water, 0.252 mL, 0.698 mmol). After 30 min stirringanother equivalent of TBAF (75% solution in water, 0.168 mL, 0.465 mmol)was added and the mixture was stirred for another 1 h. The resultingmixture was quenched with brine and then dichloromethane was added. Theisolated organic layer was washed with brine, dried over MgSO₄, filteredand concentrated. The crude residue obtained was purified by columnchromatography (Isco, 12 g cartridge) eluting with a gradient of ethylacetate in hexanes (from 0 to 100%) to give the desired compound as acolorless oil (0.101 g, 77%). LC (Method A): 1.504 min. LCMS (APCI):calcd for C₁₀H₁₃F₃NO₃S [M+H]⁺ m/z 284.06, found 284.0. ¹H NMR (CDCl₃,400 MHz) δ ppm: 1.65 (br s, 1H), 1.79 (dd, J=2.0, 14.0 Hz, 2H),2.28-2.38 (m, 2H), 2.71 (br s, 1H), 3.82-3.97 (m, 4H), 4.81 (d, J=1.2Hz, 2H).

Example 1314-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

To a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.090 g, 0.284 mmol) and4-(4-(hydroxymethyl)-5-(trifluoromethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol(0.100 g, 0.355 mmol) under nitrogen was added dry THF (5 mL). To theresulting suspension was added tri-n-butylphosphine (0.184 mL, 0.709mmol), followed by the dropwise addition of a solution of1,1′-(azodicarbonyl)dipiperidine (0.181 g, 0.709 mmol) in dry THF (2.5mL). The resulting reaction mixture was stirred at room temperature for45 min and then it was diluted with ethyl acetate and washed withsaturated aqueous NaHCO₃, dried over MgSO₄, filtered and concentrated.The crude residue obtained was purified by column chromatography (Isco,24 g cartridge) eluting with a gradient of EtOAc in DCM (from 0 to 50%)to give the title compound as a white solid (0.108 g, 65%). LC (MethodA): 2.689 min. HRMS(ESI): calcd for C₂₄H₂₂F₃N₄O₆S₂ [M+H]⁺ m/z 583.0933,found 523.0967. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.70 (d, J=13.3 Hz,2H), 2.06-2.17 (m, 2H), 3.62-3.83 (m, 4H), 3.81 (s, 3H), 4.20 (s, 3H),5.37 (s, 2H), 6.63 (d, J=9.0 Hz, 2H), 6.86 (s, 2H), 8.38 (s, 1H).

Example 1326-(4-((2-(4-Fluorotetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To an ice-cold suspension of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-(trifluoromethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol(0.052 g, 0.089 mmol) in dichloromethane (10 mL) under nitrogen wasadded DAST (0.029 mL, 0.223 mmol) dropwise. The resulting mixture wasstirred at 0° C. for 20 min and then the cooling bath was removed andthe resulting pale yellow solution was stirred at room temperature for 1h. The reaction mixture was re-cooled to 0° C., quenched by the dropwiseaddition of saturated aqueous NaHCO₃ (5 mL) and vigorously stirred for15 min to ensure complete quenching. The resulting mixture was dilutedwith dichloromethane and saturated aqueous sodium bicarbonate, then theorganic layer was separated, dried over magnesium sulfate andconcentrated under reduced pressure. The crude residue obtained waspurified by column chromatography (Isco, 24 g cartridge) eluting with agradient of EtOAc in DCM (from 0 to 50%) to give the title compound as awhite solid (0.045 g, 86%). LC (Method A): 2.492 min. LCMS (ESI): calcdfor C₂₄H₂₁F₄N₄O₅S₂ [M+H]⁺ m/z 585.0890, found 585.0904. ¹H NMR (DMSO-d₆,400 MHz) δ ppm: 2.03-2.39 (m, 4H), 3.69 (td, J=2.0, 11.7 Hz, 2H), 3.82(s, 3H), 3.85-3.92 (m, 2H), 4.20 (s, 3H), 5.43 (s, 2H), 6.65 (d, J=1.6Hz, 1H), 6.87 (s, 2H), 8.38 (s, 1H).

Example 1331-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanol

133A: 1-(4-(Hydroxymethyl)thiazol-2-yl)cyclohexanol

General Method: A solution of2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-thiazole (Example 37B,0.195 g, 0.632 mmol) in dry THF (5 mL) was cooled at −78° C. undernitrogen before n-butyllithium (1.5 M in hexanes, 0.506 mL, 0.759 mmol)was added dropwise. The resulting mixture was stirred for 15 min andthen a solution of cyclohexanone (0.075 mg, 0.759 mmol) in dry THF (1mL) was added and stirring was continued at −78° C. for 1 h. Thereaction was then quenched by the addition of saturated aqueous NH₄Cl(1.5 mL) and then the cooling bath was removed and the mixture wasdiluted with ethyl acetate. The organic phase was separated, washed(brine), dried (MgSO₄), filtered and evaporated to give a pale yellowoil. The crude1-(4-(((tert-butyldimethylsilyl)-oxy)methyl)thiazol-2-yl)cyclohexanolobtained (0.185 g, 89%) was used as such for the next step. LC (MethodA): 2.391 min. LCMS (APCI): calcd for C₁₆H₃₀NO₂SSi [M+H]⁺ m/z 328.18,found 328.2.

To a solution of crude1-(4-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)cyclo-hexanol(0.185 g, 0.480 mmol) in THF (3 mL) at room temperature was added TBAF(75% solution in water, 0.260 mL, 0.720 mmol). After 30 min anotherequivalent of TBAF (75% solution in water, 0.173 mL, 0.480 mmol) wasadded and the resulting mixture was stirred for another 1 h. Thereaction mixture was then quenched with brine and DCM was added. Theisolated organic layer was washed with brine, dried over MgSO₄, filteredand concentrated. The crude residue obtained was purified by columnchromatography (Isco, 12 g cartridge) eluting with a gradient of ethylacetate in hexanes (from 0 to 100%) to give the desired compound as acolorless oil (0.076 g, 74%). LC (Method A): 1.319 min. LCMS (APCI):calcd for C₁₀H₁₆NO₂S [M+H]⁺ m/z 214.09. found 214.2. ¹H NMR (DMSO-d₆,400 MHz) δ ppm: 1.18-1.32 (m, 1H), 1.48-1.75 (m, 7H), 1.84 (td, J=3.9,12.9 Hz, 2H), 4.50 (dd, J=0.8, 5.9 Hz, 2H), 5.22 (t, J=5.9 Hz, 1H), 5.69(s, 1H), 7.21 (s, 1H).

Example 1331-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanol

To a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.090 g, 0.284 mmol) and1-(4-(hydroxymethyl)-thiazol-2-yl)cyclohexanol (0.076 g, 0.355 mmol)under nitrogen at room temperature was added dry THF (5 mL). To theresulting suspension was added tri-n-butylphosphine (0.184 mL, 0.709mmol) and then a solution of 1,1′-(azodicarbonyl)dipiperidine (0.181 g,0.709 mmol) in dry THF (2.5 mL) was added dropwise and the resultingmixture was stirred at room temperature for 45 min. The reaction mixturewas then diluted with ethyl acetate and washed with saturated aqueousNaHCO₃, dried over MgSO₄, filtered and concentrated. The crude residueobtained was purified by column chromatography (Isco, 24 g cartridge)eluting with a gradient of ethyl acetate in dichloromethane (from 0 to50%) to give the title compound as a white solid (0.104 g, 72%). LC(Method A): 2.339 min. LCMS (ESI): calcd for C₂₄H₂₅N₄O₅S₂ [M+H]⁺ m/z513.1266, found 513.1256. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.20-1.36 (m,1H), 1.48-1.79 (m, 7H), 1.88 (td, J=3.5, 12.5 Hz, 2H), 3.81 (s, 3H),4.20 (s, 3H), 5.24 (s, 2H), 5.80 (s, 1H), 6.61 (d, J=2.0 Hz, 1H),6.82-6.84 (m, 1H), 6.98 (s, 1H), 7.64 (s, 1H), 8.37 (s, 1H).

Example 1346-(4-((2-(1-Fluorocyclohexyl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To an ice-cold suspension of1-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanol(0.050 g, 0.098 mmol) in dichloromethane (10 mL) under nitrogen wasadded DAST (0.032 mL, 0.244 mmol) dropwise. The resulting mixture wasstirred at 0° C. for 15 min and then the cooling bath was removed andthe resulting pale yellow solution was stirred at room temperature for 1h. The reaction mixture was re-cooled at 0° C., quenched by the dropwiseaddition of saturated aqueous NaHCO₃ (5 mL) and stirred vigorously for15 min to ensure complete quenching. The mixture was further dilutedwith dichloromethane and saturated aqueous sodium bicarbonate solutionand the organic layer was separated, dried over magnesium sulfate andconcentrated under reduced pressure. The crude residue obtained waspurified by column chromatography (Isco, 24 g cartridge) eluting with agradient of ethyl acetate in dichloromethane (from 0 to 50%) to give thetitle compound as a white solid (0.037 g, 74%). LC (Method A): 2.524min. LCMS (ESI): calcd for C₂₄H₂₄FN₄O₄S₂ [M+H]⁺ m/z 515.1223, found515.1203. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.30-1.46 (m, 1H), 1.56-1.73(m, 5H), 1.95-2.13 (m, 4H), 3.81 (s, 3H), 4.20 (s, 3H), 5.30 (s, 2H),6.62 (d, J=2.0 Hz, 1H), 6.83-6.85 (m, 1H), 6.99 (s, 1H), 7.88 (s, 1H),8.37 (s, 1H).

Example 1354,4-Difluoro-1-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanol

135A.1-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4,4-difluorocyclohexanol

A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 0.500 g, 1.622 mmol) in dry THF (8 mL) was cooled at −78°C. under N₂ and then n-butyllithium (1.45 M in hexanes, 0.714 mL, 1.784mmol) was added dropwise. The resulting mixture was stirred for 35 minto give a pale brown solution. To this mixture was slowly added asolution of 4,4-difluorocyclohexanone (0.218 g, 1.622 mmol) in dry THF(2 mL) and the mixture was stirred at −78° C. for 2 h to give a lightbrown solution. The reaction was then quenched by the addition ofsaturated aqueous NH₄Cl (5 mL), the cooling bath was removed and themixture was partitioned with EtOAc-water. The organic phase wasseparated, washed with brine, dried (MgSO₄) and evaporated to give apale yellow oil. This oil was purified by flash chromatography usingDCM-EtOAc as eluent to give1-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4,4-difluorocyclohexanol(0.289 g, 49.0%) as a beige solid. LC (Method A): 2.354 min. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 7.32 (s, 1H), 6.21 (s, 1H), 4.70 (s, 2H),2.21-1.99 (m, 6H), 1.86 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H).

135B. 4,4-Difluoro-1-(4-(hydroxymethyl)thiazol-2-yl)cyclohexanol

To a solution of1-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4,4-difluorocyclohexanol(0.289 g, 0.795 mmol) in dry THF (10 mL) under N₂ was addedtriethylamine trihydrofluoride (0.647 mL, 3.97 mmol) dropwise and themixture was stirred at room temperature for 16 h. The mixture was thendiluted with EtOAc and the solution was washed (saturated aqueousNaHCO₃), dried (MgSO₄) and evaporated to give4,4-difluoro-1-(4-(hydroxymethyl)thiazol-2-yl)cyclohexanol (0.164 g,83%) as a white solid. This material was used as such in the next stepwithout further purification. LC (Method A): 1.332 min. ¹H NMR (DMSO-d₆,400 MHz) δ ppm: 7.28 (s, 1H), 6.18 (s, 1H), 5.25 (t, J=5.9 Hz, 1H), 4.50(d, J=5.5 Hz, 2H), 2.21-1.99 (m, 6H), 1.88 (m, 2H).

Example 1354,4-Difluoro-1-(4-(((6-methoxy-2-(2-methoxyimidazo-[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanol

To a suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.186 g, 0.586 mmol) and4,4-difluoro-1-(4-(hydroxymethyl)thiazol-2-yl)cyclohexanol (0.146 g,0.586 mmol) in dry THF (8 mL) was added tri-n-butylphosphine (0.380 mL,1.464 mmol), followed by a solution of ADDP (0.369 g, 1.464 mmol) in THF(2 mL), added dropwise over 30 min via syringe pump. After stirring foranother 30 min, the reaction mixture was partitioned between EtOAc andsaturated aqueous NaHCO₃. The organic phase was separated, washed withbrine, dried (MgSO₄), filtered and concentrated to dryness. The residuewas purified by flash chromatography using DCM-EtOAc as eluent to give abeige solid with a yellow tinge. This solid was further triturated withacetonitrile and the resulting solid was filtered, rinsed with diethylether and dried under vacuum to give the title compound (0.250 g, 78%)as a beige solid. LC (Method A): 2.322 min. HRMS(ESI): calcd forC₂₄H₂₃F₂N₄O₅S₂ [M+H]⁺ m/z 549.1078, found 549.1101. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 8.37 (s, 1H), 7.71 (s, 1H), 6.98 (s, 1H), 6.83 (s, 1H), 6.62(d, J=1.6 Hz, 1H), 6.29 (br s, 1H), 5.26 (s, 2H), 4.20 (s, 3H), 3.80 (s,3H), 2.20-2.01 (m, 6H), 1.91 (m, 2H).

Example 1362-Methoxy-6-(6-methoxy-4-((2-(1,4,4-trifluorocyclohexyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To an ice-cold mixture of4,4-difluoro-1-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanol(0.050 g, 0.091 mmol) in dichloromethane (4 mL) under N₂ was added DAST(0.036 mL, 0.273 mmol) dropwise. The reaction mixture was stirred at 0°C. for 1 h before being quenched with saturated aqueous NaHCO₃. Theresulting mixture was extracted with EtOAc, after which the organicphase was washed with brine, dried (MgSO₄), filtered and concentrated todryness. The residue was purified by flash chromatography using agradient of 0 to 100% EtAOc in DCM to give the title compound (0.007 g,0.013 mmol, 13.95%) as a white solid. LC (Method A): 2.322 min.HRMS(ESI): calcd for C₂₄H₂₂F₃N₄O₄S₂ [M+H]⁺ m/z 551.1035, found 551.1055.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.94 (s, 1H), 6.99 (s,1H), 6.84 (d, J=0.8 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 5.31 (s, 2H), 4.20(s, 3H), 3.81 (s, 3H), 2.34-2.07 (m, 8H).

Preparation of Alcohols

The following additional alcohols were prepared according to the generalprocedure described in Example 133A;

HPLC reten- LCMS tion Calc found time [M + H]⁺ [M + H]⁺ (min)/ StructureFormula m/z m/z method NMR

C₁₂H₁₀F₃NO₂S 290.046 290.047 1.661/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:4.59 (dd, J = 0.8, 5.5 Hz, 2H), 5.37 (t, J = 5.9 Hz, 1H), 7.37-7.45 (m,3H), 7.51-7.52 (m, 1H), 7.70-7.74 (m, 2H), 8.28 (s, 1H).

C₈H₁₀F₃NO₂S 242.046 242.047 1.254/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.74 (t, J = 7.4 Hz, 3H), 1.95-2.08 (m, 1H), 2.18-2.31 (m, 1H), 4.55 (d,J = 5.5 Hz, 2H), 5.32 (t, J = 5.9 Hz, 1H), 7.23 (s, 1H), 7.46 (s, 1H).

C₉H₁₅NO₂S 202.09 202.2 1.165/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 0.73 (t,J = 7.4 Hz, 6H), 1.67-1.90 (m, 4H), 4.51 (dd, J = 0.8, 5.5 Hz, 2H), 5.21(t, J = 5.9 Hz, 1H), 5.38 (s, 1H), 7.20-7.21 (m, 1H).

C₁₂H₁₉NO₂S 242.12 242.2 1.702/A ¹H NMR (CD₃OD, 400 MHz) δ ppm: 1.00-1.32(m, 5H), 1.41-1.50 (m, 1H), 1.53 (s, 3H), 1.59-1.88 (m, 5H), 4.65 (s,2H), 7.23 (s, 1H).

C₇H₈F₃NO₂S 228.030 228.030 1.134/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.73(s, 3H), 4.55 (d, J = 5.1 Hz, 2H), 5.33 (t, J = 5.9 Hz, 1H), 7.47-7.49(m, 1H), 7.52 (br s, 1H).

C₁₁H₁₅NO₂S 226.090 226.090 1.389/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.18-0.27 (m, 2H), 0.33-0.51 (m, 6H), 1.28-1.39 (m, 2H), 4.52 (d, J =3.5 Hz, 2H), 5.22 (br s, 2H), 7.21 (s, 1H).

C₁₂H₉ClF₃NO₂S 324.01 324.0 1.905/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 4.59(d, J = 3.9 Hz, 2H), 5.34-5.42 (m, 1H), 7.48-7.55 (m, 3H), 7.75 (d, J =8.6 Hz, 2H), 8.45 (s, 1H).

C₁₂H₁₆F₃NO₂S 296.093 296.094 1.837/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.95-1.38 (m, 6H), 1.53-1.86 (m, 4H), 2.18-2.30 (m, 1H), 4.54 (d, J =3.9 Hz, 2H), 5.33 (t, J = 4.7 Hz, 1H), 7.07 (br s, 1H), 7.42 (s, 1H).

C₉H₁₅NO₃S 218.09 218.2 1.008/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.47 (s,3H), 1.94-2.10 (m, 2H), 3.14 (s, 3H), 3.15-.324 (m, 1H), 3.38-3.46 (m,1H), 4.50 (dd, J = 0.8, 5.5 Hz, 2H), 5.23 (t, J = 5.9 Hz, 1H), 5.85 (s,1H), 7.22 (s, 1H).

Examples 137 to 147

The following additional Examples have been prepared, isolated andcharacterized using the methods disclosed in Examples 133 and 134 above.

HPLC reten- LCMS tion Calc found time [M + H]⁺ [M + H]⁺ (min)/ Ex.Structure Formula m/z m/z method NMR 137

C₂₆H₁₉F₃N₄O₅S₂ 589.082 589.084 2.354/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:3.80 (s, 3H), 4.20 (s, 3H), 5.37 (s, 2H), 6.65 (d, J = 1.6 Hz, 1H),6.83- 6.84 (m, 1H), 6.99 (s, 1H), 7.38-7.42 (m, 3H), 7.71-7.76 (m, 2H),7.93 (s, 1H), 8.39 (d, J = 10.2 Hz, 2H). 138

C₂₂H₁₉F₃N₄O₅S₂ 541.082 541.080 2.258/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.75 (t, J = 7.0 Hz, 3H), 1.99-2.10 (m, 1H), 2.24-2.34 (m, 1H), 3.80 (s,3H), 4.20 (s, 3H), 5.31 (s, 2H), 6.61 (d, J = 2.0 Hz, 1H), 6.82- 6.84(m, 1H), 6.97 (d, J = 0.8 Hz, 1H), 7.35 (s, 1H), 7.88 (s, 1H), 8.37 (s,1H). 139

C₂₂H₁₈F₄N₄O₄S₂ 543.078 543.079 2.472/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.86 (t, J = 7.4 Hz, 3H), 2.34-2.47 (m, 2H), 3.80 (s, 3H), 4.20 (s, 3H),5.37 (s, 2H), 6.61 (d, J = 2.0 Hz, 1H), 6.83- 6.85 (m, 1H), 6.98 (s,1H), 8.13 (s, 1H), 8.37 (s, 1H). 140

C₂₃H₂₄N₄O₅S₂ 501.126 501.128 2.302/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.74 (t, J = 7.4 Hz, 6H), 1.71-1.92 (m, 4H), 3.80 (s, 3H), 4.20 (s, 3H),5.25 (s, 2H), 5.49 (s, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.81- 6.83 (m,1H), 6.96 (s, 1H), 7.62 (s, 1 H), 8.37 (s, 1H). 141

C₂₃H₂₃FN₄O₄S₂ 503.122 503.122 2.492/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.81 (t, J = 7.4 Hz, 6H), 1.97-2.18 (m, 4H), 3.80 (s, 3H), 4.20 (s, 3H),5.31 (s, 2H), 5.60 (d, J = 2.0 Hz, 1H), 6.82- 6.84 (m, 1H), 6.97 (s,1H), 7.84 (s, 1 H), 8.37 (s, 1H). 142

C₂₆H₂₈N₄O₅S₂ 541.157 541.157 2.423/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.82-1.20 (m, 4H), 1.43-1.83 (m, 7H), 1.47 (s, 3H), 3.79 (s, 3H), 4.20(s, 3H), 5.26 (s, 2H), 5.71 (s, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.80-6.82(m, 1H), 6.96 (d, J = 0.8 Hz, 1H), 7.61 (s, 1H), 8.36 (s, 1H). 143

C₂₁H₁₇F₃N₄O₅S₂ 527.067 527.067 2.240/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:1.77 (s, 3H), 3.81 (s, 3H), 4.20 (s, 3H), 5.30 (s, 2H), 6.62 (d, J = 2.0Hz, 1H), 6.82- 6.85 (m, 1H), 6.98 (s, 1H), 7.64 (br s, 1H), 7.91 (s,1H), 8.37 (s, 1H). 144

C₂₅H₂₄N₄O₅S₂ 525.126 525.126 2.318/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.20-0.29 (m, 2H), 0.36-0.54 (m, 6H), 1.32-1.41 (m, 2H), 3.81 (s, 3H),4.20 (s, 3H), 5.26 (s, 2H), 5.36 (s, 1H), 6.62 (d, J = 2.0 Hz, 1H),6.82- 6.83 (m, 1H), 6.98 (s, 1H), 7.63 (s, 1H), 8.36 (s, 1H). 145

C₂₆H₁₈ClF₃N₄O₅S₂ 623.043 623.044 2.462/A ¹H NMR (DMSO-d₆, 400 MHz) δppm: 3.80 (s, 3H), 4.20 (s, 3H), 5.37 (s, 2H), 6.65 (d, J = 1.6 Hz, 1H),6.83- 6.84 (m, 1H), 6.99 (s, 1H), 7.47-7.52 (m, 2H), 7.77 (d, J = 8.6Hz, 2H), 7.95 (s, 1H), 8.37 (s, 1H), 8.56 (s, 1H). 146

C₂₆H₂₅F₃N₄O₅S₂ 595.129 595.130 2.467/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:0.91-1.88 (m, 10H), 2.20-2.31 (m, 1H), 3.79 (s, 3H), 4.20 (s, 3H), 5.31(s, 2H), 6.60 (d, J = 2.0 Hz, 1H), 6.80-6.82 (m, 1H), 6.96 (s, 1H), 7.17(br s, 1H), 7.83 (s, 1H), 8.36 (s, 1H). 147

C₂₃H₂₃FN₄O₅S₂ 517.121 517.123 2.226/A ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:1.77 (d, J = 22.3 Hz, 3H), 2.22-2.44 (m, 2H), 3.15 (s, 3H), 3.29-3.36(m, 1H), 3.39-3.47 (m, 1H), 3.80 (s, 3H), 4.20 (s, 3H), 5.30 (s, 2H),6.61 (d, J = 1.6 Hz, 1H), 6.82-6.85 (m, 1H), 6.98 (d, J = 0.8 Hz, 1H),7.87 (s, 1H), 8.37 (s, 1H).

Examples 148 and 149 tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohex-3-enecarboxylateand tert-Butyl4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanecarboxylate,respectively

148A. 4-Oxocyclohexanecarboxylic acid

To a solution of ethyl 4-oxocyclohexanecarboxylate (5.00 g, 29.4 mmol)in a mixture of methanol (30 mL) and THF (125 mL) was added an aqueoussolution of NaOH (3 N, 29.4 mL, 88 mmol) and the resulting reactionmixture was heated at 60° C. for 3 h. The cooled mixture wasconcentrated under reduced pressure, the aqueous concentrate wasacidified (pH 1) with 1N HCl and the mixture was extracted with DCM(×3). The combined organic extract was washed with brine, dried overMgSO₄, filtered and concentrated to give the title compound (3.175 g,76%). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.70-1.86 (m, 2H), 2.03-2.14 (m,2H), 2.18-2.30 (m, 2H), 2.32-2.46 (m, 2H), 2.66-2.77 (m, 1H), 12.32 (brs, 1H).

148B. tert-Butyl 4-oxocyclohexanecarboxylate

To an ice-cold solution of 4-oxocyclohexanecarboxylic acid (3.175 g,22.34 mmol) in pyridine (12 mL, 148 mmol) and tert-butanol (17 mL, 178mmol) was added neat POCl₃ (3.0 mL, 32.2 mmol). The cooling bath wasthen removed and the reaction mixture was stirred at room temperaturefor 4 h. The crude mixture was then poured in water and the product wasextracted with EtOAc (3×). The combined organic extract was washed with2 N HCl (×2) and brine, dried over MgSO₄, filtered and concentrated. Thecrude residue obtained was used as such without further purification(3.02 g, 68%). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.41 (s, 9H), 1.70-1.85(m, 2H), 2.01-2.13 (m, 2H), 2.18-2.29 (m, 2H), 2.32-2.45 (m, 2H),2.63-2.75 (m, 1H).

148C. tert-Butyl4-hydroxy-4-(4-(hydroxymethyl)thiazol-2-yl)cyclohexanecarboxylate

To a solution of2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (Example 37B,0.200 g, 0.649 mmol) in dry THF (5 mL), cooled at −78° C. undernitrogen, was added n-butyllithium (1.5 M in hexanes, 0.519 mL, 0.778mmol) dropwise. The resulting mixture was stirred for 5 min before apre-cooled (−78° C.) solution of tert-butyl 4-oxocyclohexanecarboxylate(0.129 g, 0.649 mmol) in dry THF (1 mL) was cannulated into the reactionmixture. The resulting mixture was stirred at −78° C. for 1.5 h and thenthe reaction was quenched by the addition of saturated aqueous NH₄Cl (3mL). The cooling bath was then removed and the mixture was diluted withethyl acetate. The organic phase was separated, washed (brine), dried(MgSO₄), filtered and evaporated to give the crude product, tert-butyl4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylate,(0.177 g, 64%), as a pale yellow oil. This material was used as such inthe next step without further purification. LC (Method A): 2.447 min.LCMS (APCI): calcd for C₂₁H₃₈NO₄SSi [M+H]⁺ m/z 428.23, found 428.2.

To a solution of tert-butyl4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4-hydroxycyclohexanecarboxylate(0.277 g, 0.415 mmol) in THF (5 mL) at room temperature was added TBAF(75% solution in water, 0.299 mL, 0.829 mmol). The resulting mixture wasstirred for 1 h and then the reaction was quenched with brine and theresulting mixture was diluted with dichloromethane. The organic layerwas separated, washed with brine, dried over MgSO₄, filtered andconcentrated. The crude residue obtained was purified by columnchromatography (Isco, 12 g cartridge) eluting with a gradient of ethylacetate in dichloromethane (from 0 to 100%) to give the desired compoundas viscous, colorless oil which was a mixture of cis- and trans-isomers(0.073 g, 56%). LC (Method A): 1.768, 1.789 min. LCMS (APCI): calcd forC₁₅H₂₄NO₄S [M+H]⁺ m/z 314.14, found 314.2. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 1.40 (s, 9H), 1.52-1.93 (m, 7H), 2.01-2.12 (m, 1H), 2.17-2.28 (m,1H), 4.50 (s, 2H), 5.23 (t, J=5.1 Hz, 1H), 5.78 (d, J=11.7 Hz, 1H), 7.24(d, J=11.3 Hz, 1H).

Examples 148 and 149 tert-Butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohex-3-enecarboxylateand tert-Butyl4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanecarboxylate,respectively

To a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.070 g, 0.221 mmol) and tert-butyl4-hydroxy-4-(4-(hydroxymethyl)thiazol-2-yl)cyclohexanecarboxylate (0.069g, 0.221 mmol) was added dry THF (5 mL) and the flask was flushed withnitrogen. To the resulting suspension was added tri-n-butylphosphine(0.143 mL, 0.551 mmol), followed by the dropwise addition of a solutionof 1,1′-(azodicarbonyl)dipiperidine (0.141 g, 0.551 mmol) in dry THF(2.5 mL). The resulting reaction mixture was stirred at room temperaturefor 1.5 h and then it was diluted with ethyl acetate, washed withsaturated aqueous NaHCO₃, dried over MgSO₄, filtered and concentrated.The crude residue obtained was purified by flash chromatography (Isco,24 g cartridge) using a 0-100% gradient of EtOAc in DCM to give twofractions. Fraction 1 was obtained as a solid which was furthertriturated with MeOH to give (after filtration, washing with MeOH anddrying in vacuo) tert-butyl4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohex-3-enecarboxylate(0.011 g, 8%) as a white solid. LC (Method A): 2.567 min. HRMS(ESI)calcd for C₂₉H₃₁N₄O₆S₂ [M+H]⁺ m/z 595.168, found 595.168. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 1.38 (s, 9H), 1.64 (m, 1H), 2.00 (m, 1H),2.25-2.65 (m, 5H), 3.77 (s, 3H), 4.17 (s, 3H), 5.23 (s, 2H), 6.57 (d,J=1.57 Hz, 1H), 6.61 (br s, 1H), 6.80 (s, 1H), 6.97 (s, 1H), 7.66 (s,1H), 8.33 (s, 1H). Fraction 2 was further purified by preparative HPLC(Method A) to give tert-butyl4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanecarboxylateas a white solid which was a mixture of cis- and trans-isomers (0.010 g,7%). LC (Method A): 2.320 min. HRMS(ESI): calcd for C₂₉H₃₃N₄O₇S₂ [M+H]⁺m/z 613.1791, found 613.1789. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.39 (s,4.5H), 1.41 (s, 4.5H), 1.61-1.98 (m, 7H), 2.04-2.16 (m, 1H), 2.21-2.31(m, 1H), 3.80 (s, 3H), 4.21 (s, 3H), 5.24 (s, 1H), 5.25 (s, 1H), 5.87(br s, 1H), 6.60 (d, J=2.0 Hz, 0.5H), 6.61 (d, J=2.0 Hz, 0.5H),6.81-6.84 (m, 1H), 6.97 (d, J=0.8 Hz, 0.5H), 6.98 (d, J=0.8 Hz, 0.5H),7.65 (s, 0.5H), 7.68 (s, 0.5H), 8.36 (s, 0.5H), 8.37 (s, 0.5H).

Example 1504-Hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanecarboxylicacid

To a solution of tert-butyl4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanecarboxylate(0.486 g, 0.587 mmol) in dichloromethane (20 mL) at room temperature wasadded TFA (2.261 mL, 29.3 mmol) and the mixture was stirred for 1.5 h.The resulting mixture was diluted with toluene and the volatiles werethen removed under reduced pressure. The orange oil obtained wasco-evaporated with methanol (×2) to give the crude title compound (0.297g, 91%) as an orange solid which was a mixture of cis- andtrans-isomers. This material was used as such for the next step withoutfurther purification. LC (Method A): 2.110, 2.142 min. HRMS(ESI): calcdfor C₂₅H₂₅N₄O₇S₂ [M+H]⁺ m/z 557.1165, found 557.1169. ¹H NMR (DMSO-d₆,400 MHz) δ ppm: 1.60-2.15 (m, 8H), 2.24-2.35 (m, 1H), 2.21-2.31 (m, 1H),3.81 (s, 3H), 4.21 (s, 3H), 5.24 (d, J=5.4 Hz, 1H), 5.26 (s, 1H), 5.90(s, 0.5H), 5.92 (s, 0.5H), 6.61 (d, J=2.0 Hz, 0.5H), 6.62 (d, J=2.0 Hz,0.5H), 6.82-6.85 (m, 1H), 6.99 (d, J=0.4 Hz, 0.5H), 7.00 (d, J=0.8 Hz,0.5H), 7.66 (s, 0.5H), 7.67 (s, 0.5H), 8.38 (s, 1H).

Example 151(4-Hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexyl)(pyrrolidin-1-yl)methanone

To a solution of4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanecarboxylicacid (0.025 g, 0.045 mmol) and pyrrolidine (3.71 μl, 0.045 mmol) in DMF(1 mL) was added DIEA (0.039 mL, 0.225 mmol), followed by HATU (0.0214g, 0.056 mmol). The resulting reaction mixture was stirred at roomtemperature for 3 h and then it was diluted with ethyl acetate andwashed with saturated aqueous NaHCO₃, and brine. The organic layer wasseparated, dried over MgSO₄, filtered and concentrated. The cruderesidue obtained was purified by preparative HPLC (Method A) to give twofractions. Fraction 1 was identified as Isomer A of the title compound(0.008 g, 25%). LC (Method A): 2.236 min. HRMS(ESI): calcd forC₂₉H₃₂N₅O₆S₂ [M+H]⁺ m/z 610.1794, found 610.1777. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 1.60-1.91 (m, 11), 2.28-2.36 (m, 2H), 3.24 (t, J=7.0 Hz,2H), 3.45 (t, J=6.7 Hz, 2H), 3.80 (s, 3H), 4.19 (s, 3H), 5.25 (s, 2H),5.80 (br s, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.81-6.84 (m, 1H), 7.00 (s,1H), 7.72 (s, 1H), 8.38 (s, 1H). Fraction 2 was re-purified bypreparative HPLC (Method A) to give pure Isomer B of the title compound(0.004 g, 14%). LC (Method A): 2.301 min. HRMS(ESI): calcd forC₂₉H₃₂N₅O₆S₂ [M+H]⁺ m/z 610.1794, found 610.1791. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 1.51-1.60 (m, 2H), 1.70-2.04 (m, 11H), 3.27 (t, J=6.7 Hz,2H), 3.48 (t, J=6.7 Hz, 2H), 3.81 (s, 3H), 4.20 (s, 3H), 5.23 (s, 2H),5.90 (s, 1H), 6.60 (d, J=1.6 Hz, 1H), 6.82-6.84 (m, 1H), 6.97 (d, J=0.8Hz, 1H), 7.64 (s, 1H), 8.37 (s, 1H).

Example 152N-(Cyanomethyl)-4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N-methylcyclohexanecarboxamide

The title compound was prepared from4-hydroxy-4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)cyclohexanecarboxylicacid and 2-(methylamino)acetonitrile according to the method describedin Example 151 above. The crude product mixture was separated into itstwo isomers using preparative HPLC (Method A). Isomer A. LC (Method A):2.143 min. HRMS(ESI): calcd for C₂₈H₂₉N₆O₆S₂ [M+H]⁺ m/z 609.1590, found609.1581. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 1.61-1.88 (m, 7H), 2.27-2.34(m, 1H), 2.78-2.89 (m, 1H), 3.11 (s, 3H), 3.81 (s, 3H), 4.20 (s, 3H),4.36 (s, 2H), 5.26 (s, 2H), 5.88 (br s, 1H), 6.62 (d, J=2.0 Hz, 1H),6.81-6.85 (m, 1H), 7.00 (d, J=0.8 Hz, 1H), 7.72 (s, 1H), 8.37 (s, 1H).Isomer B. LC (Method A): 2.177 min. HRMS(ESI): calcd for C₂₈H₂₉N₆O₆S₂[M+H]⁺ m/z 609.1590, found 609.1580. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:1.49-1.62 (m, 2H), 1.74-1.90 (m, 4H), 1.96-2.10 (m, 2H), 2.72-2.85 (m,1H), 3.13 (s, 3H), 3.81 (s, 3H), 4.20 (s, 3H), 4.37 (s, 2H), 5.23 (s,2H), 5.94 (br s, 1H), 6.59 (d, J=1.6 Hz, 1H), 6.82-6.85 (m, 1H), 6.97(s, 1H), 7.65 (s, 1H), 8.37 (s, 1H).

Example 1536-(4-((2-(4-(4-Bromophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

153A. 4-(4-Bromophenyl)tetrahydro-2H-pyran-4-carbonitrile

A solution of 2-(4-bromophenyl)acetonitrile (1.00 g, 5.10 mmol) in dryTHF (5.85 mL) was treated with 17 M sodium hydroxide (9.00 mL, 153mmol), tetrabutylammonium hydrogen sulfate (0.173 g, 0.510 mmol) and1-chloro-2-(2-chloroethoxy)ethane (0.628 mL, 5.36 mmol). The reactionmixture was heated to reflux for 4 h, then the cooled mixture wasdiluted with EtOAc, washed with 1N HCl, water and saturated aqueousNaHCO₃. The organic phase was dried over MgSO₄, filtered andconcentrated to dryness. The residue was then purified by flashchromatography using a gradient of 0 to 100% EtOAc in hexanes to give4-(4-bromophenyl)tetrahydro-2H-pyran-4-carbonitrile (1.11 g, 82%) as aclear yellow oil. LC (Method F): 2.080 min. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 7.66 (ddd, J=2.0, 2.7, 8.6 Hz, 2H), 7.52 (ddd, J=2.0, 2.7, 8.6 Hz),4.01 (m, 2H), 3.64 (m, 2H), 2.12-1.99 (m, 4H).

153B. 4-(4-Bromophenyl)tetrahydro-2H-pyran-4-carboxamide

4-(4-Bromophenyl)tetrahydro-2H-pyran-4-carbonitrile (1.09 g, 4.10 mmol)was stirred in concentrated sulphuric acid (3 mL) at room temperaturefor 40 h. The mixture was then poured onto ice and the resultingsuspension was filtered and the filter-cake washed thoroughly with wateruntil the pH of the wash was neutral. The resulting white solid wasrinsed with hexanes and then dried under reduced pressure to give4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxamide (1.065 g, 92%). LC(Method F): 1.835 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 7.53 (dt, J=2.5,9.0 Hz, 2H), 7.32 (dt, J=2.5, 9.0 Hz, 2H), 7.23 (br s, 1H), 7.06 (br s,1H), 3.73 (dt, J=3.7, 11.7 Hz, 2H), 3.46 (dt, J=2.0, 11.7 Hz, 2H), 2.40(d, J=13.3 Hz, 2H), 1.77 (m, 2H).

153C. 4-(4-Bromophenyl)tetrahydro-2H-pyran-4-carbothioamide

To a stirred solution of4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxamide (1.00 g, 3.52 mmol)in THF (12 mL) was added Lawesson's reagent (0.712 g, 1.760 mmol) all atonce and the reaction mixture was heated to reflux for 6 h. The cooledreaction mixture was then concentrated to near dryness and partitionedwith EtOAc-saturated aqueous NaHCO₃. The organic phase was dried(MgSO₄), filtered and concentrated to dryness and the residue waspurified by flash chromatography using hexanes-EtOAc as eluent to give4-(4-bromophenyl)tetrahydro-2H-pyran-4-carbothioamide as a white solid(0.771 g, 73.0%). LC (Method F): 1.993 min. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 9.70 (s, 1H), 8.92 (s, 1H), 7.54 (ddd, J=2.0, 2.7, 8.6 Hz, 2H),7.40 ((ddd, J=2.0, 2.7, 8.6 Hz, 2H), 3.59 (m, 4H), 2.60 (m, 2H), 2.07(m, 2H).

153D. Ethyl2-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate

To a mixture of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carbothioamide(0.725 g, 2.415 mmol) in isopropanol (10 mL) was added ethylbromopyruvate (0.365 mL, 2.90 mmol) and the reaction mixture was heatedto reflux for 2.75 h. The cooled mixture was partitioned between EtOAcand saturated aqueous NaHCO₃ and the organic phase was washed withbrine, dried (MgSO₄), filtered and concentrated to dryness. The residuewas purified by flash chromatography using a gradient of 0 to 100% EtOAcin hexanes to give ethyl2-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate(0.288 g, 30.1%) as a clear, colorless oil. LC (Method F): 2.320 min. ¹HNMR (DMSO-d₆, 400 MHz) δ ppm: 8.46 (s, 1H), 7.55 (dt, J=2.4, 9.0 Hz,2H), 7.38 (dt, J=2.4, 9.0 Hz, 2H), 4.29 (q, J=7.0 Hz, 2H), 3.70 (m, 2H),3.57 (m, 2H), 2.56 (m, 2H), 2.35 (m, 2H), 1.29 (t, J=7.0 Hz, 3H).

153E.(2-(4-(4-Bromophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

To an ice-cold solution of ethyl2-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate(0.288 g, 0.727 mmol) in THF (3.6 mL) was added LiBH₄ (0.0314 g, 1.441mmol) all at once, followed by MeOH (0.058 mL, 1.441 mmol). Theresulting mixture was stirred at 0° C. for 5 min and then at ambienttemperature for 16 h. The mixture was then re-cooled at 0° C. andcarefully quenched by the dropwise addition of saturated aqueous NH₄Cl.The resulting mixture was extracted with ethyl acetate, after which theorganic phase was washed with brine, dried (MgSO₄), filtered andevaporated to dryness. The obtained residue was purified by flashchromatography using a gradient of 0 to 100% EtOAc in hexanes to give(2-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol(0.226 g, 89%) as a white solid. LC (Method F): 2.111 min. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 7.52 (m, 2H), 7.35 (m, 3H), 5.28 (t, J=5.7 Hz,1H), 4.53 (dd, J=1.2, 5.9 Hz, 2H), 3.72 (m, 1H), 3.69 (t, J=4.3 Hz, 1H),3.55 (m, 2H), 2.55 (m, 1H), 2.29 (m, 2H).

Example 1536-(4-((2-(4-(4-Bromophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a flame-dried flask containing6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.035 g, 0.110 mmol) and(2-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol(0.039 g, 0.110 mmol) was added dry THF (4 mL), followed bytri-n-butylphosphine (0.072 mL, 0.276 mmol). To the resulting suspensionwas added a solution of ADDP (0.070 g, 0.276 mmol) in THF (1 mL)dropwise over 30 min via syringe pump. After stirring for 1.5 h, thereaction mixture was diluted with EtOAc, then washed with 1N HCl,saturated aqueous NaHCO₃, water and brine. The organic phase was dried(MgSO₄) and evaporated and the crude material was triturated with DMSO,filtered, rinsed with acetonitrile and dried in vacuo to give the titlecompound (0.035 g, 48.6%) as a beige solid. LC (Method F): 2.732 min.HRMS(ESI): calcd for C₂₉H₂₆BrN₄O₅S₂ [M+H]⁺ m/z 653.0528, found 653.0530.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.36 (s, 1H), 7.75 (s, 1H), 7.52 (d,J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 6.98 (s, 1H), 6.83 (s, 1H), 6.62(d, J=2.0 Hz, 1H), 5.29 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 3.74-3.70(m, 2H), 3.56 (m, 2H), 2.57 (m, 2H), 2.35-2.28 (m, 2H).

Example 1546-(4-((2-(4-(4-Chlorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

154A.(2-(4-(4-Chlorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example153 above. LC (Method F): 2.076 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.40 (m, 4H), 7.34 (m, 1H), 5.28 (t, J=5.7 Hz, 1H), 4.53 (dd, J=1.2, 5.9Hz, 2H), 3.71 (m, 2H), 3.55 (m, 2H), 2.54 (m, 2H), 2.30 (m, 2H).

Example 1546-(4-((2-(4-(4-Chlorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 153 above and was isolated as a solid. LC (Method F): 2.728 min.HRMS(ESI): calcd for C₂₉H₂₆ClN₄O₅S₂ [M+H]⁺ m/z 609.1028, found 609.1077.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.75 (s, 1H), 7.41 (m,4H), 6.98 (d, J=0.8 Hz, 1H), 6.83 (dd, J=0.8, 1.6 Hz, 1H), 6.62 (d,J=1.6 Hz, 1H), 5.29 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 3.75-3.70 (m,2H), 3.56 (m, 2H), 2.58 (m, 2H), 2.32 (m, 2H).

Example 1556-(4-((2-(4-(3-Chlorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

155A.(2-(4-(3-Chlorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example153 above. LC (Method F): 2.057 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.40-7.35 (m, 4H), 7.32-7.29 (m, 1H), 5.29 (m, 1H), 4.53 (s, 1H), 3.74(m, 1H), 3.71 (t, J=4.3 Hz, 1H), 3.56 (dd, J=2.3, 9.4 Hz, 1H), 3.53 (dd,J=2.3, 9.4 Hz, 1H), 2.56 (dd, J=2.0, 11.7 Hz, 2H), 2.33 (dd, J=3.9, 9.4Hz, 1H), 2.29 (m, 1H).

Example 1556-(4-((2-(4-(3-Chlorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 153 above and was isolated as a solid. LC (Method F): 2.679 min.HRMS(ESI): calcd for C₂₉H₂₆ClN₄O₅S₂ [M+H]⁺ m/z 609.1033, found 609.1042.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.36 (s, 1H), 7.77 (s, 1H), 7.42-7.35(m, 3H), 7.30 (m, 1H), 6.98 (d, J=0.8 Hz, 1H), 6.83 (dd, J=0.8, 1.6 Hz,1H), 6.62 (d, J=1.6 Hz, 1H), 5.30 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H),3.73 (dt, J=4.3, 12.1 Hz, 2H), 3.55 (m, 2H), 2.60 (m, 2H), 2.37-2.30 (m,2H).

Example 1566-(4-((2-(4-(2-Fluorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

156A.(2-(4-(2-Fluorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example153 above. LC (Method F): 1.948 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.48 (dt, J=2.0, 8.2 Hz, 1H), 7.38-7.33 (m, 1H), 7.31 (m, 1H), 7.23 (dt,J=1.6, 7.8 Hz, 1H), 7.13 (ddd, J=1.2, 8.2, 12.9 Hz, 1H), 5.27 (br s,1H), 4.52 (s, 2H), 3.73-3.62 (m, 4H), 2.44 (m, 4H).

Example 1566-(4-((2-(4-(2-Fluorophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 153 above and was isolated as a solid. LC (Method F): 2.633 min.HRMS(ESI): calcd for C₂₉H₂₆FN₄O₅S₂ [M+H]⁺ m/z 593.1329, found 593.1356.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.73 (s, 1H), 7.51 (dt,J=1.6, 8.2 Hz, 1H), 7.37 (m, 1H), 7.25 (dt, J=1.2, 7.4 Hz, 1H), 7.15(ddd, J=1.2, 8.2, 12.9 Hz, 1H), 6.98 (s, 1H), 6.83 (dd, J=0.8, 2.0 Hz,1H), 6.61 (d, J=2.0 Hz, 1H), 5.28 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H),3.74-3.63 (m, 4H), 2.58-2.42 (m, 4H).

Example 1572-Methoxy-6-(6-methoxy-4-((2-(4-(p-tolyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

157A. (2-(4-(p-Tolyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example153 above. LC (Method F): 2.043 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.29 (t, J=1.2 Hz, 1H), 7.27 (m, 2H), 7.14 (d, J=7.8 Hz, 2H), 5.26 (t,J=5.5 Hz, 1H), 4.53 (d, J=4.3 Hz, 2H), 3.72-3.66 (m, 2H), 3.57 (m, 1H),3.55 (dd, J=2.7, 9.0 Hz, 1H), 2.53 (m, 2H), 2.29 (m, 2H), 2.25 (s, 3H).

Example 1572-Methoxy-6-(6-methoxy-4-((2-(4-(p-tolyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 153 above and was isolated as a solid. LC (Method F): 2.662 min.HRMS(ESI): calcd for C₃₀H₂₉N₄O₅S₂ [M+H]⁺ m/z 589.1579, found 589.1593.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.71 (s, 1H), 7.29 (d,J=8.2 Hz, 2H), 7.14 (d, J=8.2 Hz, 2H), 6.98 (s, 1H), 6.83 (dd, J=0.8,1.6 Hz, 1H), 6.26 (d, J=2.0 Hz, 1H), 5.28 (s, 2H), 4.20 (s, 3H), 3.80(s, 3H), 3.71 (m, 2H), 3.57 (m, 2H), 2.56 (m, 2H), 2.32 (m, 2H), 2.25(s, 3H).

Example 1582-Methoxy-6-(6-methoxy-4-((2-(4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

158A.(2-(4-(3-Methoxyphenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example153 above. LC (Method F): 1.953 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.32 (s, 1H), 7.26 (t, J=8.0 Hz, 1H), 6.96 (dd, J=1.2, 7.8 Hz, 1H), 6.88(m, 1H), 6.80 (dd, J=2.3, 8.0 Hz, 1H), 5.28 (t, J=5.7 Hz, 1H), 4.53 (d,J=5.5 Hz, 2H), 3.72 (m, 2H), 3.72 (s, 3H), 3.54 (m, 2H), 2.53 (m, 2H),2.29 (ddd, J=3.5, 9.2, 13.3 Hz, 2H).

Example 1582-Methoxy-6-(6-methoxy-4-((2-(4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 153 above and was isolated as a solid. LC (Method F): 2.675 min.HRMS(ESI): calcd for C₃₀H₂₉N₄O₆S₂ [M+H]⁺ m/z 605.1529, found 605.1544.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 836 (s, 1H), 7.74 (s, 1H), 7.25 (t,J=8.0 Hz, 1H), 6.98 (m, 2H), 6.90 (m, 1H), 6.82 (m, 1H), 6.81 (m, 1H),6.62 (d, J=1.6 Hz, 1H), 5.29 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 3.73(m, 2H), 3.71 (s, 3H), 3.56 (m, 2H), 2.57 (m, 2H), 2.32 (m, 2H).

Example 1592-Methoxy-6-(6-methoxy-4-((2-(4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

159A.(2-(4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example153 above. LCMS (APCI): calcd for C₁₆H₂₀NO₃S [M+H]⁺ m/z 306.12, found306.20.

Example 1592-Methoxy-6-(6-methoxy-4-((2-(4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 153 above and was isolated as a solid. LC (Method F): 2.440 min.HRMS(ESI): calcd for C₃₀H₂₉N₄O₆S₂ [M+H]⁺ m/z 605.1529, found 605.1557.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.36 (s, 1H), 7.70 (s, 1H), 7.32 (d,J=8.6 Hz, 2H), 6.98 (s, 1H), 6.88 (d, J=9.0 Hz, 2H), 6.83 (s, 1H), 6.62(d, J=1.6 Hz, 1H), 5.28 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 3.72 (s,3H), 3.70 (m, 2H), 3.60 (m, 2H), 2.55 (m, 2H), 2.30 (m, 2H).

Example 160 Methyl4-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoate

160A.2-(4-(4-Bromophenyl)tetrahydro-2H-pyran-4-yl)-4-(((tert-butyldimethylsilyl)-oxy)methyl)thiazole

To a stirred solution of(2-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol(Example 153E, 0.163 g, 0.460 mmol) and imidazole (0.047 g, 0.690 mmol)in DCM (7.5 mL) at ambient temperature was addedtert-butylchlorodimethylsilane (0.087 g, 0.575 mmol). The reactionmixture was stirred overnight, then quenched with MeOH and concentratedto dryness. The residue was purified by column chromatography usinghexanes-EtOAc as eluent to give2-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(0.214 g, 99%) as a clear, colorless oil. LC (Method A): 2.683 min. ¹HNMR (DMSO-d₆, 400 MHz) δ ppm: 7.46 (d, J=8.8 Hz, 2H), 7.32 (s, 1H), 7.28(d, J=8.8 Hz, 2H), 4.66 (s, 2H), 3.65 (m, 2H), 3.49 (m, 2H), 2.48 (m,2H), 2.23 (m, 2H), 0.81 (s, 9H), 0.00 (s, 6H).

160B. Methyl4-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoateand Methyl4-(4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoate

To a mixture of Pd(OAc)₂ (0.002 g, 9.14 μmol) and Xantphos (0.0106 g,0.018 mmol) was added as a solution of2-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(0.214 g, 0.457 mmol) in Et₃N (2 mL, 14.35 mmol) after which MeOH (0.185mL, 4.57 mmol) was added. The reaction mixture was placed under highvacuum and then back-filled with CO (g) (using a CO-filled balloon). Thevessel was sealed and then heated with stirring at 70° C. (oil bathtemperature) for 24 h. The cooled mixture was filtered through CELITE®and the filter-cake was washed with additional MeOH. The filtrate wasevaporated and the residue was purified by flash chromatography usinghexanes-EtOAc as eluent to give methyl4-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoate(0.052 g, 25.4%) as a clear, colorless oil. LC (Method A): 2.552 min.LCMS (APCI): calcd for C₂₃H₃₄NO₄SSi [M+H]⁺ m/z 448.20, found 448.20.Further elution afforded methyl4-(4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoate(0.029 g, 19.04%) as a white solid. LC (Method A): 1.769 min. LCMS(APCI): calcd for C₁₇H₂₁NO₄S [M+H]⁺ m/z 334.11, found 334.20.

Example 160 Methyl4-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoate

The title compound was prepared according to the method described inExample 153 above and was isolated as a solid. LC (Method A): 2.588 min.HRMS(ESI): calcd for C₃₁H₂₉N₄O₇S₂ [M+H]⁺ m/z 633.1478, found 633.1493.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.36 (s, 1H), 7.91 (d, J=8.6 Hz, 2H),7.76 (s, 1H), 7.56 (d, J=8.2 Hz, 2H), 6.97 (s, 1H), 6.82 (m, 1H), 6.61(d, J=1.6 Hz, 1H), 5.30 (s, 2H), 4.20 (s, 3H), 3.82 (s, 3H), 3.80 (s,3H), 3.74 (dt, J=3.9, 12.1 Hz, 2H), 3.57 (m, 2H), 2.62 (m, 2H), 2.36 (m,2H).

Example 1614-(4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N,N-dimethylbenzamide

161A.4-(4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N,N-dimethylbenzamide

To a stirred solution of methyl4-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoate(Example 160B, 0.863 g, 1.928 mmol) in MeOH (10 mL) was added 1 N sodiumhydroxide (2.121 mL, 2.121 mmol). The reaction mixture was stirred atambient temperature for 2 h and then at 55° C. for 1 h. The cooledmixture was neutralized (pH 7) with 1N HCl and stirring was continuedfor 10 min. The resulting slurry was filtered and the residue was washedwith water and then dried in vacuo to give4-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoicacid (0.305 g, 0.703 mmol, 36.5%) as a white solid. LC (Method A): 2.418min. LCMS (APCI): calcd for C₂₂H₃₂NO₄SSi [M+H]⁺ m/z 434.18, found434.20.

To a stirred solution of4-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)benzoicacid (0.100 g, 0.231 mmol) in DMF (3 mL) was added dimethylamine (0.115mL, 0.231 mmol), DIEA (0.201 mL, 1.153 mmol) and HATU (0.088 g, 0.231mmol). After stirring at room temperature for 2 h, the mixture waspartitioned between EtOAc and saturated aqueous NaHCO₃. The organicphase was separated, dried (MgSO₄), filtered and concentrated todryness. The residue was purified by flash chromatography usingDCM-EtOAc as eluent to give4-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N,N-dimethylbenzamide(0.088 g, 83%) as a white solid. LC (Method A): 2.343 min. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 7.43 (m, 2H), 7.37 (m, 3H), 4.73 (d, J=0.8 Hz,2H), 4.34 (t, J=5.1 Hz, 1H), 3.74 (m, 2H), 3.56 (m, 2H), 3.44 (m, 1H),2.95 (br s, 2H), 2.88 (br s, 2H), 2.58 (m, 2H), 2.33 (m, 2H), 0.87 (s,9H), 0.06 (s, 6H).

161B.4-(4-(4-(Hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N,N-dimethylbenzamide

To a stirred solution of4-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N,N-dimethylbenzamide(0.088 g, 0.191 mmol) in THF (1 mL) was added triethylaminetrihydrofluoride (0.156 mL, 0.955 mmol) and the mixture was stirred atroom temperature for 4 h. The resulting mixture was partitioned betweenEtOAc and saturated aqueous NaHCO₃ and the organic phase was separated,dried (MgSO₄), filtered and concentrated to dryness. The residue waspurified by flash chromatography using DCM-EtOAc as eluent to give4-(4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N,N-dimethylbenzamide(0.044 g, 66.5%) as a clear, colorless oil. LC (Method A): 1.492 min.LCMS (APCI): calcd for C₁₈H₂₃N₂O₃S [M+H]⁺ m/z 347.14, found 347.20.

Example 1614-(4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N,N-dimethylbenzamide

To a suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.040 g, 0.127 mmol) and4-(4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N,N-dimethylbenzamide(0.044 g, 0.127 mmol) in dry THF (8 mL) was added tri-n-butylphosphine(0.082 mL, 0.318 mmol) and then a solution of ADDP (0.080 g, 0.318 mmol)in THF (2 mL) was added dropwise over 30 min via syringe pump. Afterstirring for another 30 min, the reaction mixture was partitionedbetween EtOAc and saturated aqueous NaHCO₃. The organic phase wasseparated, washed with brine, dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by flash column chromatographyusing 0 to 10% of MeOH:NH₄OH (9:1) in DCM as eluent to give the slightlyimpure product. The obtained material was further triturated with MeCNand the resulting slurry was filtered, washed with a minimum volume ofMeCN and dried under reduced pressure to give the title compound (0.040g, 48.8%) as a white solid. LC (Method A): 2.297 min. HRMS(ESI): calcdfor C₃₂H₃₂N₅O₆S₂ [M+H]⁺ m/z 646.1794 found, 646.1870. ¹H NMR (DMSO-d₆,400 MHz) δ ppm: 8.36 (s, 1H), 7.76 (s, 1H), 7.40 (dd, J=8.4, 38.5 Hz,4H), 6.97 (d, J=0.8 Hz, 1H), 6.83 (dd, J=0.8, 1.6 Hz, 1H), 6.62 (d,J=1.6 Hz, 1H), 5.30 (s, 2h), 4.20 (s, 3H), 3.80 (s, 3H), 3.75 (m, 2H),3.57 (m, 2H), 2.95 (br s, 3H), 2.87 (br s, 3H), 2.61 (m, 2H), 2.35 (m,2H).

Example 1622-Methoxy-6-(6-methoxy-4-((2-(4-phenyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

162A. (2-(4-Phenyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example153 above. LC (Method F): 1.936 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.39 (m, 2H), 7.34 (m, 3H), 7.22 (m, 1H), 5.27 (t, J=5.9 Hz, 1H), 4.54(m, 2H), 3.72 (m, 2H), 3.58 (dd, J=2.3, 9.4 Hz, 1H), 3.55 (dd, J=2.3,9.4 Hz, 1H), 2.56 (m, 2H), 2.33 (m, 1H), 2.30 (dd, J=3.9, 9.4 Hz, 1H).

Example 1622-Methoxy-6-(6-methoxy-4-((2-(4-phenyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 153 above and was isolated as a solid. LC (Method F): 2.651 min.HRMS(ESI): calcd for C₂₉H₂₇N₄O₅S₂ [M+H]⁺ m/z 575.1423, found 575.1442.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.36 (s, 1H), 7.73 (s, 1H), 7.41 (m,2H), 7.33 (m, 2H), 7.23 (m, 1H), 6.98 (d, J=0.8 Hz, 1H), 6.83 (dd,J=0.8, 1.6 Hz, 1H), 6.63 (d, J=2.0 Hz, 1H), 5.30 (s, 2H), 4.20 (s, 3H),3.80 (s, 3H), 3.73 (dt, J=4.3, 11.3 Hz, 2H), 3.57 (m, 2H), 2.60 (m, 2H),2.34 (m, 2H).

Example 1636-(4-((2-(3-(4-Chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

163A. 3-(4-Chlorophenyl)tetrahydrofuran-3-carbonitrile

To a stirred suspension of NaH (60% in oil, 0.792 g, 19.79 mmol) (Note:previously washed twice with hexanes and dried in vacuo) in NMP (17 mL)cooled at −20° C. was added dropwise a mixture of2-(4-chlorophenyl)acetonitrile (1.00 g, 6.60 mmol) and1-chloro-2-(chloromethoxy)ethane (0.851 g, 6.60 mmol) in diethyl ether(4 mL). The mixture was then allowed to warm to room temperature over 24h. The reaction was slowly quenched with ice-water and the resultingmixture was extracted with ether (×3). The combined organic layer waswashed with water and brine, dried (MgSO₄), concentrated and evaporated.The residue was purified by flash chromatography using hexanes-EtOAc aseluent to give 3-(4-chlorophenyl)tetrahydrofuran-3-carbonitrile (0.621g, 45.3%) as an orange oil. LC (Method F): 1.970 min. ¹H NMR (DMSO-d₆,400 MHz) δ ppm: 7.54 (m, 4H), 4.39 (d, J=9.0 Hz, 1H), 4.06 (dd, J=5.7,8.2 Hz, 2H), 3.84 (d, J=8.6 Hz, 1H), 2.77 (m, 1H), 2.48 (m, 1H).

163B. 3-(4-Chlorophenyl)tetrahydrofuran-3-carboxamide

A solution of 3-(4-chlorophenyl)tetrahydrofuran-3-carbonitrile (0.615 g,2.96 mmol) in concentrated H₂SO₄ (4 mL) was stirred overnight at ambienttemperature. The reaction mixture was then carefully quenched withcrushed ice and the mixture was stirred for 1 h. The resultingsuspension was filtered and the filter-cake was washed with water, thendiethyl ether and finally it was dried under reduced pressure to give3-(4-chlorophenyl)-tetrahydrofuran-3-carboxamide (0.466 g, 69.7%) as abeige solid: LC (Method F): 1.699 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.40 (m, 2H), 7.32 (m, 2H), 7.30 (br s, 1H), 7.07 (br s, 1H), 4.45 (d,J=8.2 Hz, 1H), 3.79 (m, 1H), 3.75 (d, J=7.8 Hz, 1H), 3.72 (d, J=8.6 Hz,1H), 2.82 (ddd, J=5.1, 7.4, 12.5 Hz, 1H), 2.10 (m, 1H).

163C. 3-(4-Chlorophenyl)tetrahydrofuran-3-carbothioamide

To a stirred solution of 3-(4-chlorophenyl)tetrahydrofuran-3-carboxamide(0.450 g, 1.994 mmol) in THF (15 mL) was added2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide(0.403 g, 0.997 mmol) all at once and the mixture was heated to refluxfor 2 h. The resulting mixture was then concentrated to near dryness andthe concentrate was partitioned between EtOAc and saturated aqueousNaHCO₃. The organic phase was separated, dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by flashchromatography using hexanes-EtOAc as eluent to give3-(4-chlorophenyl)-tetrahydrofuran-3-carbothioamide (0.356 g, 73.9%) asa white solid. LC (Method F): 1.864 min. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 9.71 (br s, 1H), 9.00 (br s, 1H), 7.43 (m, 4H), 4.43 (d, J=9.0 Hz,1H), 3.99 (d, J=8.6 Hz, 1H), 3.84-3.71 (m, 2H), 2.91 (m, 1H), 2.33 (m,1H).

163D. Ethyl2-(3-(4-chlorophenyl)tetrahydrofuran-3-yl)thiazole-4-carboxylate

To a mixture of 3-(4-chlorophenyl)tetrahydrofuran-3-carbothioamide(0.345 g, 1.427 mmol) in i-PrOH (10 mL) was added ethyl bromopyruvate(0.215 mL, 1.713 mmol) and the reaction mixture was heated to reflux for3 h. The cooled mixture was partitioned between EtOAc and saturatedaqueous NaHCO₃ and the organic phase was washed with brine, dried(MgSO₄), filtered and concentrated to dryness. The residue was purifiedby flash chromatography using a gradient of 0 to 100% EtOAc in hexanesto give ethyl2-(3-(4-chlorophenyl)tetrahydrofuran-3-yl)thiazole-4-carboxylate (0.200g, 41.5%) as a clear, yellow oil. LC (Method F): 2.248 min. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 8.45 (s, 1H), 7.41 (m, 4H), 4.58 (d, J=8.6 Hz,1H), 4.29 (q, J=7.0 Hz, 2H), 4.11 (d, J=8.6 Hz, 1H), 3.97-3.86 (m, 2H),2.98 (m, 1H), 2.59 (m, 1H), 1.29 (t, J=7.0 Hz, 3H).

163E. (2-(3-(4-Chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methanol

To an ice-cold solution of ethyl2-(3-(4-chlorophenyl)tetrahydrofuran-3-yl)thiazole-4-carboxylate (0.200g, 0.592 mmol) in THF (3 mL) was added LiBH₄ (0.026 g, 1.184 mmol) allat once, followed by MeOH (0.048 mL, 1.184 mmol). The resulting mixturewas stirred at 0° C. for 5 min and then at ambient temperature for 4 h.The mixture was then re-cooled at 0° C., quenched by dropwise additionof saturated aqueous NH₄Cl and then extracted with ethyl acetate. Theorganic phase was separated, washed with brine, dried (MgSO₄), filteredand concentrated to dryness. The residue was purified by columnchromatography using a gradient of 0 to 100% EtOAc in hexanes to give(2-(3-(4-chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methanol (0.146g, 83%) as a clear, colorless oil: LC (Method F): 1.990 min. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 7.39 (m, 4H), 7.32 (s, 1H), 5.28 (br s, 1H),4.54 (d, J=8.6 Hz, 1H), 4.51 (s, 2H), 4.09 (d, J=8.2 Hz, 1H), 3.95-3.84(m, 2H), 2.95 (ddd, J=4.7, 7.0, 12.1 Hz, 1H), 2.55 (m, 1H).

Example 1636-(4-((2-(3-(4-Chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.032 g, 0.101 mmol) and(2-(3-(4-chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methanol (0.030g, 0.101 mmol) in dry THF (8 mL) was added tri-n-butylphosphine (0.066mL, 0.254 mmol) and then a solution of ADDP (0.064 g, 0.254 mmol) in THF(2 mL) was added dropwise over 30 min via syringe pump. After stirringfor another 30 min, the reaction mixture was partitioned between EtOAcand saturated aqueous NaHCO₃. The organic phase was separated, washedwith brine, dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by flash chromatography using DCM-EtOAc as eluentto give the product as a yellow-beige solid. This material was furthertriturated with acetonitrile, the mixture was filtered and thefilter-cake was rinsed with diethyl ether and then dried under vacuum.This gave pure6-(4-((2-(3-(4-chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.041 g, 67.9%) as a white solid. LC (Method F): 2.619 min. HRMS(ESI):calcd for C₂₈H₂₄ClN₄O₅S₂ [M+H]⁺ m/z 595.0877, found 595.0888. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.74 (s, 1H), 7.40 (s, 4H), 6.98(s, 1H), 6.83 (d, J=0.8 Hz, 1H), 6.60 (d, J=1.6 Hz, 1H), 5.26 (s, 2H),4.59 (d, J=8.6 Hz, 1H), 4.20 (s, 3H), 4.12 (d, J=8.6 Hz, 1H), 3.98-3.87(m, 2H), 3.80 (s, 3H), 2.99 (m, 1H), 2.62-2.55 (m, 1H).

Example 1642-Methoxy-6-(6-methoxy-4-((2-(3-(p-tolyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

164A. (2-(3-(p-Tolyl)tetrahydrofuran-3-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example163 above. LC (Method F): 1.995 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.28 (s, 1H), 7.22 (m, 2H), 7.14 (d, J=8.2 Hz, 2H), 5.26 (t, J=5.7 Hz,1H), 4.55 (d, J=8.2 Hz, 1H), 4.50 (dd, J=0.8, 5.9 Hz, 2H), 4.07 (d,J=8.2 Hz, 1H), 3.93-3.83 (m, 2H), 2.94 (ddd, J=4.7, 7.2, 12.1 Hz, 1H),2.53 (m, 1H).

Example 1642-Methoxy-6-(6-methoxy-4-((2-(3-(p-tolyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 163 above and was isolated as a solid. LC (Method F): 2.628 min.HRMS(ESI): calcd for C₂₉H₂₇N₄O₅S₂ [M+H]⁺ m/z 575.1423, found 575.1441.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.70 (s, 1H), 7.25 (d,J=8.2 Hz, 2H), 7.15 (d, J=7.8 Hz, 2H), 6.98 (s, 1H), 6.83 (s, 1H), 6.61(d, J=1.6 Hz, 1H), 5.26 (s, 2H), 4.59 (d, J=8.2 Hz, 1H), 4.20 (s, 3H),4.10 (d, J=8.2 Hz, 1H), 3.96-3.86 (m, 2H), 3.80 (s, 3H), 2.98 (m, 1H),2.56 (dt, J=8.2, 12.5 Hz, 1H), 2.26 (s, 3H).

Example 1656-(4-((2-(3-(3-Chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

165A. (2-(3-(3-Chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example163 above. LC (Method F): 2.004 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.37-7.27 (m, 5H), 5.25 (t, J=5.7 Hz, 1H), 4.53 (d, J=8.6 Hz, 1H), 4.48(d, J=5.1 Hz, 2H), 4.07 (d, J=8.6 Hz, 1H), 3.89 (m, 1H), 3.83 (q, J=7.8Hz, 1H), 2.93 (ddd, J=4.7, 7.4, 12.5 Hz, 1H), 2.54 (dt, J=8.2, 12.5 Hz,1H).

Example 1656-(4-((2-(3-(3-Chlorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 163 above and was isolated as a solid. LC (Method F): 2.650 min.HRMS(ESI): calcd for C₂₈H₂₄ClN₄O₅S₂ [M+H]⁺ m/z 595.0877, found 595.0896.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.65 (s, 1H), 8.02 (d, J=9.4 Hz, 1H),7.98 (m, 2H), 7.93 (s, 1H), 7.55-7.49 (m, 3H), 7.26 (s, 1H), 7.19 (d,J=9.0 Hz, 1H), 6.78 (dd, J=2.1, 10.0 Hz, 2H), 5.44 (s, 2H), 3.80 (s,3H), 2.53 (s, 3H).

Example 1666-(4-((2-(3-(2-Fluorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

166A. (2-(3-(2-Fluorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example163 above. LC (Method F): 1.900 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.52 (dt, J=1.6, 7.8 Hz, 1H), 7.38 (m, 1H), 7.28 (s, 1H), 7.23 (dt,J=1.2, 7.6 Hz, 1H), 7.18 (ddd, J=1.2, 8.2, 11.7 Hz, 1H), 5.26 (t, J=5.9Hz, 1H), 4.58 (dd, J=3.1, 8.6 Hz, 1H), 4.48 (d, J=5.5 Hz, 2H), 4.09 (d,J=8.6 Hz, 1H), 3.91 (m, 2H), 2.97 (m, 1H), 2.55 (m, 1H).

Example 1666-(4-((2-(3-(2-Fluorophenyl)tetrahydrofuran-3-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 163 above and was isolated as a solid. LC (Method F): 2.627 min.HRMS(ESI): calcd for C₂₈H₂₄FN₄O₅S₂ [M+H]⁺ m/z 579.1172, found 579.1202.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.36 (s, 1H), 7.70 (s, 1H), 7.55 (dt,J=1.6, 7.8 Hz, 1H), 7.39 (m, 1H), 7.25 (dt, J=1.2, 7.4 Hz, 1H), 7.20(ddd, J=0.8, 8.2, 11.7 Hz, 1H), 6.97 (s, 1H), 6.82 (d, J=0.8 Hz, 1H),6.59 (d, J=1.6 Hz, 1H), 5.23 (s, 2H), 4.62 (dd, J=2.7, 8.6 Hz, 1H), 4.20(s, 3H), 4.12 (d, J=8.6 Hz, 1H), 3.94 (m, 1H), 3.80 (s, 3H), 3.01 (m,1H), 2.58 (dt, J=8.4, 12.5 Hz, 1H).

Example 1672-Methoxy-6-(6-methoxy-4-((2-(4-methyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

167A. Methyl 4-methyltetrahydro-2H-pyran-4-carboxylate

To a stirred solution of methyl tetrahydro-2H-pyran-4-carboxylate (0.926mL, 6.94 mmol) in anhydrous THF (20 mL), at −78° C. under nitrogen, wasadded LDA (1 M in xx, 8.32 mL, 8.32 mmol) dropwise over 30 min. Themixture was then allowed to warm to 0° C. for 15 min and then it wasre-cooled to −78° C. and iodomethane (0.867 mL, 13.87 mmol) was addeddropwise over 5 min. The solution was stirred at −78° C. for 30 min andthen at 0° C. for 3 h before being quenched with saturated aqueous NH₄Cland extracted with ethyl acetate. The organic phase was washed withwater and brine, dried (MgSO₄), filtered and evaporated to give acolorless oil. This material was purified by flash chromatography usinga gradient of 0 to 100% EtOAc in hexanes to give methyl4-methyltetrahydro-2H-pyran-4-carboxylate (0.666 g, 60.7%) as a clear,colorless oil. LC (Method F): 1.549 min. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 3.67 (dt, J=4.5, 12.2 Hz, 2H), 3.64 (s, 3H), 3.33 (m, 2H), 1.91 (m,2H), 1.43 (dd, J=3.9, 9.8 Hz, 1H), 1.40 (dd, J=3.9, 9.8 Hz, 1H), 1.16(s, 3H).

167B. 4-Methyltetrahydro-2H-pyran-4-carboxylic acid

To a stirred solution of methyl4-methyltetrahydro-2H-pyran-4-carboxylate (0.600 g, 3.79 mmol) in MeOH(15 mL) was added 1 N sodium hydroxide (7.59 mL, 7.59 mmol) and themixture was stirred at ambient temperature for 24 h. The mixture wasthen concentrated to remove the MeOH and the aqueous concentrate waswashed with EtOAc. The aqueous phase was acidified to pH 1 usingconcentrated HCl and then extracted with EtOAc. The organic extract wasdried (MgSO₄), filtered and concentrated to dryness to give4-methyltetrahydro-2H-pyran-4-carboxylic acid (0.316 g, 57.8%) as aclear, colorless oil. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 12.21 (s, 1H),3.67 (dt, J=4.5, 12.1 Hz, 2H), 3.35 (m, 2H), 1.89 (m, 2H), 1.36 (ddd,J=3.9, 9.8, 13.7 Hz, 2H), 1.15 (s, 3H).

167C. 4-Methyltetrahydro-2H-pyran-4-carboxamide

To a stirred solution of 4-methyltetrahydro-2H-pyran-4-carboxylic acid(0.300 g, 2.081 mmol) in DCM (5 mL) was added oxalyl chloride (0.364 mL,4.16 mmol) and the reaction mixture was stirred for 1 h before beingconcentrated to dryness. The residue was taken up in THF (1 mL) and thissolution was added with stirring to concentrated aqueous ammonia (5 mL)at 0° C. The mixture was stirred at 0° C. for 2 min and then at ambienttemperature for 30 min before being diluted with water and extractedwith EtOAc. The aqueous phase was concentrated to dryness to give awhite solid which was suspended in EtOAc (20 mL) and the mixture heatedwith stirring at 60° C. for 20 min and then hot-filtered. The filtratewas combined with the original organic extract and evaporated to drynessto give 4-methyltetrahydro-2H-pyran-4-carboxamide (0.255 g, 86%) as awhite solid which was used as such in the next step. ¹H NMR (DMSO-d₆,400 MHz) δ ppm: 7.18 (br s, 1H), 6.86 (br s, 1H), 3.61 (m, 2H), 3.37 (m,2H), 1.92 (m, 2H), 1.33 (dd, J=3.9, 9.4 Hz, 1H), 1.30 (m, 1H), 1.09 (s,3H).

167D. 4-Methyltetrahydro-2H-pyran-4-carbothioamide

To a stirred solution of 4-methyltetrahydro-2H-pyran-4-carboxamide(0.250 g, 1.746 mmol) in THF (4 mL) was added Lawesson's reagent (0.353g, 0.873 mmol) and the reaction mixture was heated at reflux for 6 h.The cooled mixture was concentrated to near dryness then partitionedwith EtOAc-saturated aqueous NaHCO₃. The organic phase was separated andthe aqueous phase was saturated with (solid) NaCl and back-extractedwith EtOAc. The combined organic extract was dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by flash column usinghexanes-EtOAc as eluent to give4-methyltetrahydro-2H-pyran-4-carbothioamide (0.052 g, 18.7%) as a whitesolid. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 9.61 (br s, 1H), 8.79 (br s,1H), 3.58 (m, 2H), 3.48 (m, 2H), 2.13 (m, 2H), 1.52 (m, 2H), 1.18 (s,3H).

167E. Ethyl 2-(4-methyltetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate

To a mixture of 4-methyltetrahydro-2H-pyran-4-carbothioamide (0.052 g,0.327 mmol) in i-PrOH (5 mL) was added ethyl bromopyruvate (0.049 mL,0.392 mmol) and the reaction mixture was heated to reflux for 3 h. Thecooled mixture was partitioned between EtOAc-saturated aqueous NaHCO₃and the organic phase was washed with brine, dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by flashchromatography using a gradient of 0 to 100% EtOAc in hexanes to giveethyl 2-(4-methyltetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (44 mg,0.172 mmol, 52.8% yield) as a clear, colorless oil. The crude materialwas used as such without further purification. LC (Method F): 2.003 min.

167F. (2-(4-Methyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol

To an ice-cold solution of ethyl2-(4-methyltetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (0.045 g,0.176 mmol) in THF (1 mL) was added LiBH₄ (0.008 g, 0.352 mmol) all atonce, followed by MeOH (0.014 mL, 0.352 mmol). The resulting mixture wasstirred at 0° C. for 5 min and then at ambient temperature for 16 h. Themixture was then re-cooled at 0° C. and quenched by slow addition ofsaturated aqueous NH₄Cl. The resulting mixture was extracted with ethylacetate, after which the organic phase was washed with brine, dried(MgSO₄), filtered and concentrated to dryness. The residue was purifiedby flash chromatography using a gradient of 0 to 100% EtOAc in hexanesto give (2-(4-methyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol(0.028 g, 74.5% yield) as a clear, colorless oil. LC (Method F): 1.564min.

Example 1672-Methoxy-6-(6-methoxy-4-((2-(4-methyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.042 g, 0.131 mmol) and(2-(4-methyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (0.028 g,0.131 mmol) in dry THF (4 mL) was added tri-n-butylphosphine (0.085 mL,0.328 mmol) and the resulting suspension was charged with a solution ofADDP (0.083 g, 0.328 mmol) in THF (1 mL), added dropwise over 30 min viasyringe pump. After stirring for 1.5 h, the reaction mixture was dilutedwith EtOAc and then washed with 1N HCl, saturated aqueous NaHCO₃, waterand brine. The organic solution was evaporated and the obtained cruderesidue was dissolved in DMSO and purified by preparative HPLC (ZORBAX®SB-C18 column 21.2×100 mm, eluted with CH₃CN-water-0.1% TFA).Product-containing fractions were concentrated to dryness and theresidue was lyophilized from CH₃CN-water to give the title compound(0.038 g, 0.074 mmol, 56.5%) as an amorphous white solid. LC (Method F):2.590 min. HRMS(ESI): calcd for C₂₄H₂₅N₄O₅S₂ [M+H]⁺ m/z 513.1266, found513.1305. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.74 (s, 1H),6.99 (d, J=0.8 Hz, 1H), 6.83 (dd, J=0.8, 1.6 Hz, 1H), 6.62 (d, J=2.0 Hz,1H), 5.28 (s, 2H), 4.20 (s, 3H), 3.81 (s, 3H), 3.70 (m, 2H), 3.53 (dd,J=3.1, 7.8 Hz, 1H), 3.50 (dd, J=3.1, 7.8 Hz, 1H), 2.12 (m, 2H), 1.74 (m,2H), 1.38 (s, 3H).

Example 1686-(4-((2-(Chroman-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

168A. (2-(Chroman-4-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example167. LC (Method F): 1.894 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 7.30 (m,1H), 7.16 (m, 1H), 7.09 (dd, J=1.2, 7.4 Hz, 1H), 6.86 (dd, J=1.2, 7.4Hz, 1H), 6.82 (m, 1H), 5.29 (t, J=5.7 Hz, 1H), 4.56 (m, 1H), 4.54 (dd,J=1.2, 5.9 Hz, 2H), 4.24 (m, 1H), 4.13-4.08 (m, 1H), 2.32-2.28 (m, 2H).

Example 1686-(4-((2-(Chroman-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 167 above and was isolated as a solid. LC (Method F): 2.638 min.HRMS(ESI): calcd for C₂₇H₂₃N₄O₅S₂ [M+H]⁺ m/z 547.1110, found 547.1130.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.72 (s, 1H), 7.18 (m,1H), 7.13 (m, 1H), 6.98 (d, J=0.8 Hz, 1H), 6.88-6.82 (m, 3H), 6.61 (d,J=2.0 Hz, 1H), 5.29 (s, 2H), 4.63 (t, J=5.1 Hz, 1H), 4.25 (m, 1H), 4.20(s, 3H), 4.13-4.08 (m, 1H), 3.80 (s, 3H), 2.34 (q, J=5.5 Hz, 2H).

Example 1696-(4-((2-(2H-Chromen-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

169A. 4-(4-(Hydroxymethyl)thiazol-2-yl)chroman-4-ol

The alcohol was prepared according to the method described in Example118. LC (Method F): 1.519 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 7.33 (d,J=1.2 Hz, 1H), 7.15 (m, 1H), 7.02 (m, 1H), 6.81 (m, 2H), 6.73 (s, 1H),5.22 (t, J=5.9 Hz, 1H), 4.46-4.41 (m, 3H), 4.30 (m, 1H), 2.50 (m, 1H),2.17 (ddd, J=2.7, 5.7, 13.7 Hz, 1H).

169B.4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)chroman-4-ol

The title compound was prepared from6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H) and 4-(4-(hydroxymethyl)thiazol-2-yl)chroman-4-ol accordingto the method described in Example 118 and was isolated as a solid. LC(Method A): 2.478 min. HRMS(ESI): calcd for C₂₇H₂₃N₄O₆S₂ [M+H]⁺ m/z563.1059, found 563.1059. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.36 (s, 1H),7.75 (s, 1H), 7.17 (m, 1H), 7.05 (m, 1H), 6.95 (s, 1H), 6.83 (m, 4H),6.55 (m, 1H), 5.20 (s, 2H), 4.45 (m, 1H), 4.31 (m, 1H), 4.20 (s, 3H),3.77 (s, 3H), 2.54 (m, 1H), 2.21 (m, 1H).

Example 1696-(4-((2-(2H-Chromen-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To an ice-cold solution of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)chroman-4-ol(0.025 g, 0.044 mmol) in DCM (5 mL) was added DAST (0.018 mL, 0.133mmol) and the reaction mixture was stirred at 0° C. for 5 min and thenat room temperature for 20 min. The reaction was then quenched at 0° C.with saturated aqueous NaHCO₃ and diluted with DCM. The organic phasewas separated, dried (MgSO4), filtered and concentrated to dryness. Theresidue was purified by preparative HPLC (Method A). Theproduct-containing fractions were evaporated and the residue waslyophilized from MeCN-water to give6-(4-((2-(2H-chromen-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.007 g, 28.9%) as an amorphous white solid. LC (Method F): 2.206 min.HRMS(ESI): calcd for C₂₇H₂₁N₄O₅S₂ [M+H]⁺ m/z 545.0953, found 545.0956.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.90 (dd, J=1.6, 7.8 Hz,1H), 7.89 (s, 1H), 7.23 (m, 1H), 7.02 (d, J=0.8 Hz, 1H), 6.94 (dt,J=1.2, 7.4 Hz, 1H), 6.90 (dd, J=1.2, 7.8 Hz, 1H), 6.85 (d, J=0.8 Hz,1H), 6.67 (d, J=2.0 Hz, 1H), 6.57 (t, J=4.1 Hz, 1H), 5.39 (s, 2H), 4.85(d, J=3.9 Hz, 2H), 4.20 (s, 3H), 3.81 (s, 3H).

Example 170(R)-N-(4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide

170A.(R)-N-(Dihydro-2H-pyran-4(3H)-ylidene)-2-methylpropane-2-sulfinamide

To a stirred solution of dihydro-2H-pyran-4(3H)-one (2.40 g, 23.97 mmol)in THF (50 mL) at room temperature under nitrogen was added titanium(IV) ethoxide (8.80 mL, 42.0 mmol) followed by(R)-(+)-2-methylpropane-2-sulfinamide (2.58 g, 21.29 mmol). The reactionwas stirred at room temperature for 3 h and then it was quenched bypouring it into a mixture of cold saturated aqueous NaHCO₃ (50 mL) andEtOAc (50 mL), with rapid stirring. The resulting slurry was filteredand the residue rinsed with EtOAc. The aqueous layer of the filtrate wasseparated and re-extracted with EtOAc. The combined organics were dried(Na₂SO₄) and concentrated to give a light yellow oil. Flashchromatography (Isco/0-100% EtOAc-hexane) afforded(R)-N-(dihydro-2H-pyran-4(3H)-ylidene)-2-methylpropane-2-sulfinamide(2.045 g, 47.2%) as a clear, colorless oil which crystallized onstanding in vacuo. This material was used as such in the next step. LC(Method A): 1.199 min. HRMS(ESI): calcd for C₉H₁₈NO₂S [M+H]⁺ m/z204.106. found 204.106.

170B.(R)-N-(4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide

A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 2.58 g, 8.37 mmol) in dry THF (40 mL) was cooled at −78°C. under N₂ and then 1.45 M n-butyllithium (6.93 mL, 10.04 mmol) wasadded dropwise. The resulting mixture was stirred for 30 min to give alight yellow-brown solution. To this mixture was added a solution of(R)-N-(dihydro-2H-pyran-4(3H)-ylidene)-2-methylpropane-2-sulfinamide(2.042 g, 10.04 mmol) in dry THF (10 mL) over 5 min and the mixture waskept at −78° C. for 2 h. The reaction was then quenched by the additionof saturated aqueous NH₄Cl (10 mL) and then the cooling bath was removedand the mixture was partitioned with EtOAc-water. The organic phase wasseparated, the aqueous phase was back-extracted with EtOAc and thecombined organic phase was washed (brine), dried (Na₂SO₄) and evaporatedto give a pale yellow oil. Flash chromatography (Isco/0-5% [10%NH₄OH-MeOH]-DCM) afforded(R)-N-(4-(4-(((tert-butyldimethylsilyl)oxy)-methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide(3.05 g, 84%) as a nearly colorless gum. This material was used as suchin the next step. LC (Method A): 2.394 min. HRMS(ESI): calcd forC₁₉H₃₇N₂O₃S₂Si [M+H]⁺ m/z 433.201. found 433.203. ¹H NMR (400 MHz,DMSO-d₆): δ 7.35 (s, 1H), 5.60 (s, 1H), 4.65 (s, 2H), 3.69 (m, 2H), 3.49(m, 1H), 3.38 (m, 1H), 2.27 (m, 1H), 2.09 (m, 3H), 1.02 (s, 9H), 0.81(s, 9H), 0.00 (s, 6H).

170C.(R)-N-(4-(4-(Hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide

To a solution of(R)-N-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide(3.045 g, 7.04 mmol) in dry THF (25 mL) under N₂ was added triethylaminetrihydrofluoride (3.44 mL, 21.11 mmol) dropwise and the mixture wasstirred at room temperature for 2 days. The mixture was then dilutedwith DCM and the solution was washed (saturated aqueous NaHCO₃), dried(Na₂SO₄) and evaporated to give(R)-N-(4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide(2.074 g, 93%) as a colorless oil which crystallized on standing invacuo. This material was essentially pure and was used as such in thenext step. LC (Method A): 1.426 min. HRMS(ESI): calcd for C₁₃H₂₃N₂O₃S₂[M+H]⁺ m/z 319.115, found 319.115. ¹H NMR (400 MHz, DMSO-d₆): δ 7.31 (s,1H), 5.58 (s, 1H), 5.22 (t, J=5.87 Hz, 1H), 4.47 (d, J=5.87 Hz, 2H),3.69 (m, 2H), 3.49 (m, 1H), 3.39 (m, 1H), 2.25 (m, 1H), 2.09 (m, 3H),1.03 (s, 9H).

Example 170(R)-N-(4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.200 g, 0.630 mmol) and(R)-N-(4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide(0.241 g, 0.756 mmol), then the flask was flushed with N₂ and dry THF (8mL) was added. To the resulting suspension was addedtri-n-butylphosphine (0.409 mL, 1.576 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (0.402 g, 1.576 mmol) in dry THF (5 mL)was added dropwise (via syringe pump) over 30 min. The resulting mixturewas stirred at room temperature for another 1 h and then it was dilutedwith EtOAc, washed (saturated aqueous NaHCO₃, H₂O, brine), dried(Na₂SO₄) and evaporated to give a pale yellow gum. Flash chromatography(Isco/0-5% [10% NH₄OH-MeOH]-DCM) gave a solid which was triturated witha minimum volume of MeCN. The resulting suspension was filtered and thefilter-cake was washed with a little MeCN and then dried in vacuo togive(R)-N-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide(0.294 g, 76%) as a white solid. LC (Method A): 2.240 min. HRMS(ESI):calcd for C₂₇H₃₂N₅O₆S₃ [M+H]⁺ m/z 618.151; found 618.150. ¹H NMR (400MHz, DMSO-d₆): δ 8.33 (s, 1H), 7.77 (s, 1H), 6.95 (s, 1H), 6.80 (s, 1H),6.59 (d, J=1.57 Hz, 1H), 5.72 (s, 1H), 5.25 (s, 2H), 4.17 (s, 3H), 3.77(s, 3H), 3.73 (m, 2H), 3.55 (m, 1H), 3.46 (m, 1H), 2.31 (m, 1H), 2.18(m, 3H), 1.08 (s, 9H).

Example 171N-(4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfonamide

To a solution of(R)-N-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide(0.050 g, 0.081 mmol) in DCM (3 mL) under N₂ was added 70%3-chloroperoxybenzoic acid (0.030 g, 0.121 mmol) all at once and theresulting yellow mixture was stirred at room temperature for 6 h. Thereaction mixture was then diluted with DCM and this mixture was washed(0.1 N NaOH, saturated aqueous NaHCO₃, brine), dried (Na₂SO₄) andevaporated to give a dark green solid. Flash chromatography (Isco/0-100%acetone-hexane) affordedN-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfonamide(0.004 g, 7.80%) as an off-white solid. LC (Method A): 2.258 min.HRMS(ESI): calcd for C₂₇H₃₂N₅O₇S₃ [M+H]⁺ m/z 634.146; found 634.147. ¹HNMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 7.75 (s, 1H), 7.17 (s, 1H), 6.90(s, 1H), 6.76 (s, 1H), 6.55 (d, J=1.96 Hz, 1H), 5.21 (s, 2H), 4.14 (s,3H), 3.74 (s, 3H), 3.70 (m, 2H), 3.47 (m, 2H), 2.24 (m, 4H), 1.12 (s,9H).

Example 1724-(4-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-amine,HCl

Method A: To a solution of(R)-N-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide(0.0103 g, 0.017 mmol) in THF (1 mL) was added 6 M aqueous HCl (0.050mL) and the mixture was stirred at room temperature in a sealed vial for30 min. The mixture was then diluted with DCM, washed (saturated aqueousNaHCO₃), dried (Na₂SO₄) and evaporated to give a gum. This material waspurified by preparative HPLC (Method A) to give a solid which waslyophilized from MeCN-water to give4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-amine,TFA (0.005 g, 48.0%) as a white solid. LC (Method A): 1.911 min.HRMS(ESI): calcd for C₂₃H₂₄N₅O₅S₂ [M+H]⁺ m/z 514.122; found 514.122. ¹HNMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 7.87 (s, 1H), 6.93 (s, 1H), 6.78(s, 1H), 6.55 (d, J=1.96 Hz, 1H), 5.25 (s, 2H), 4.14 (s, 3H), 3.74 (s,3H), 2.26 (m, 4H), 2.20-2.04 (m, 6H).

Method B: To a suspension of(R)-N-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropane-2-sulfinamide(0.280 g, 0.453 mmol) in THF (12 mL) was added 6 M aqueous HCl (0.755mL, 4.53 mmol) and the mixture was stirred at room temperature in asealed vial for 30 min. The mixture was subsequently filtered and thefilter-cake was washed with a small amount of THF and then it was driedin vacuo to give4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-amine,HCl (0.249 g, 100% yield) as a white solid. A small portion of thissolid was partitioned with EtOAc-saturated aqueous NaHCO₃ (a minimumvolume of MeOH was added to help solubilize) and the organic phase wasseparated, dried (Na₂SO₄) and evaporated to give a white solid. Flashchromatography (Isco/0-10% [10% NH₄OH-MeOH]-DCM) afforded4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-amineas a white solid. LC (Method A): 2.038 min. HRMS(ESI): calcd forC₂₃H₂₄N₅O₅S₂ [M+H]⁺ m/z 514.122; found 514.120. ¹H NMR (400 MHz,DMSO-d₆): δ 8.30 (s, 1H), 7.57 (s, 1H), 6.91 (s, 1H), 6.76 (m, 1H), 6.56(d, J=1.96 Hz, 1H), 5.18 (s, 2H), 4.14 (s, 3H), 3.74 (s, 3H), 3.70 (dt,J=2.35, 10.96 Hz, 2H), 3.63 (dt, J=4.30, 11.35 Hz, 2H), 2.05 (m, 2H),1.50 (d, J=12.52 Hz, 2H).

Example 173 tert-Butyl(2-((4-(4-(((6-methoxy-2-(2-methoxyimidazo-[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-thiazol-2-yl)tetrahydro-2H-pyran-4-yl)amino)-2-oxoethyl)carbamate

To a mixture of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-amine(0.035 g, 0.068 mmol) and 2-((tert-butoxycarbonyl)amino)acetic acid(0.013 g, 0.076 mmol) in DMF (2 mL) was added DIEA (0.048 mL, 0.275mmol), followed by HATU (0.029 g, 0.076 mmol). The resulting pale yellowsolution was stirred at room temperature for 16 h and then it wasdiluted with water (6 mL), the resulting slurry was filtered and theresidue was washed with water. The wet residue was then partitioned withDCM-saturated aqueous NaHCO₃ and the organic phase was separated, dried(Na₂SO₄) and evaporated to give a colorless gum. Flash chromatography(Isco/0-10% [10% NH₄OH-MeOH]-DCM) gave tert-butyl(2-((4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)amino)-2-oxoethyl)carbamate(0.029 g, 62.9%) as a colorless gum which was lyophilized fromMeCN-water to give a white solid. LC (Method A): 2.292 min. HRMS(ESI):calcd for C₃₀H₃₅N₆O₈S₂ [M+H]⁺ m/z 671.196; found 671.195. ¹H NMR (400MHz, DMSO-d₆): δ 8.38 (s, 1H), 8.34 (s, 1H), 7.69 (s, 1H), 7.01 (s, 1H),6.93 (t, J=5.87 Hz, 1H), 6.84 (m, 1H), 6.20 (t, J=1.96 Hz, 1H), 5.25 (s,2H), 4.20 (s, 3H), 3.81 (s, 3H), 3.74 (m, 2H), 3.63-3.57 (m, 4H), 2.32(m, 2H), 2.12 (m, 2H), 1.38 (s, 9H).

Example 1742-(Dimethylamino)-N-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-thiazol-2-yl)tetrahydro-2H-pyran-4-yl)acetamide

To a suspension of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-amine,HCl (Example 172, 0.035 g, 0.064 mmol) and 2-(dimethylamino)acetic acid(7.44 mg, 0.070 mmol) in DMF (1.5 mL) was added DIEA (0.056 mL, 0.318mmol), followed by HATU (0.027 g, 0.070 mmol). The resulting pale yellowsolution was stirred at room temperature for 1 h and then the mixturewas diluted with water (3 mL), the resulting slurry was filtered and theresidue was washed with water. The wet residue was then partitioned withDCM-saturated aqueous NaHCO₃ and the organic phase was separated, dried(Na₂SO₄) and evaporated to give a colorless gum. Flash chromatography(Isco/0-10% [10% NH₄OH-MeOH]-DCM) gave2-(dimethylamino)-N-(4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)acetamide(0.026 g, 68.2%) as a solid. LC (Method A): 2.026 min. HRMS(ESI): calcdfor C₂₇H₃₁N₆O₆S₂ [M+H]⁺ m/z 599.175; found 599.176. ¹H NMR (400 MHz,DMSO-d₆): δ 8.31 (s, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 6.77(s, 1H), 6.55 (d, J=1.96 Hz, 1H), 5.18 (s, 2H), 4.14 (s, 3H), 3.75 (s,3H), 3.70 (m, 2H), 3.51 (t, J=10.96 Hz, 2H), 2.88 (s, 2H), 2.30 (m, 2H),2.12 (m, 2H), 2.20 (s, 6H), 2.07 (m, 2H).

Example 1752-Methoxy-6-(6-methoxy-4-((2-(2-phenylpropan-2-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

175A. 2-Methyl-2-phenylpropanamide

To a stirred solution of 2-methyl-2-phenylpropanoic acid (2.00 g, 12.18mmol) in DCM (29 mL) was added oxalyl chloride (2.132 mL, 24.36 mmol)and the reaction mixture was stirred for 1 h at room temperature beforebeing evaporated to dryness. The resulting residue was then taken up inTHF (6 mL) and was added with stirring to ice-cold concentrated aqueousammonia (29 mL). After 2 min the cooling bath was removed and themixture was stirred at room temperature for 30 min. The resultingmixture was diluted with water and then extracted with EtOAc. Theorganic phase was washed with brine, dried (MgSO₄), filtered andconcentrated to dryness to give 2-methyl-2-phenylpropanamide (0.763 g,38.4%) as a white solid. This material was used as such in the nextstep. LC (Method F): 1.563 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.35-7.29 (m, 4H), 7.20 (m, 1H), 6.86 (br s, 2H), 1.42 (s, 6H).

175B. 2-Methyl-2-phenylpropanethioamide

A solution of 2-methyl-2-phenylpropanamide (0.756 g, 4.63 mmol) andLawesson's reagent (0.937 g, 2.316 mmol) in THF (5 mL) was heated toreflux for 2 h. The cooled reaction mixture was partitioned withEtOAc-saturated aqueous NaHCO₃ and the organic phase was separated,dried (MgSO₄), filtered and evaporated. The residue was purified byflash chromatography using hexanes-EtOAc as eluent to give2-methyl-2-phenylpropanethioamide (0.452 g, 54.4%) as a white solid. LC(Method F): 1.784 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 9.54 (br s, 1H),8.50 (br s, 1H), 7.38-7.35 (m, 2H), 7.30 (m, 2H), 7.21 (m, 1H), 1.56 (s,6H).

175C. Ethyl 2-(2-phenylpropan-2-yl)thiazole-4-carboxylate

To a mixture of 2-methyl-2-phenylpropanethioamide (0.445 g, 2.482 mmol)in i-PrOH (5 mL) was added ethyl bromopyruvate (0.375 mL, 2.98 mmol) andthe reaction mixture was heated to reflux for 3 h. The cooled mixturewas partitioned with EtOAc-saturated aqueous NaHCO₃ and the organicphase was separated, washed with brine, dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by columnchromatography using a gradient of 0 to 100% EtOAc in hexanes to giveethyl 2-(2-phenylpropan-2-yl)thiazole-4-carboxylate (524 mg, 77% yield)as a clear, colorless oil. LC (Method F): 2.206 min. ¹H NMR (DMSO-d₆,400 MHz) δ ppm: 8.41 (s, 1H), 7.36-7.31 (m, 4H), 7.28-7.23 (m, 1H), 4.29(q, J=7.0 Hz, 2H), 1.79 (s, 6H), 1.30 (t, J=7.0 Hz, 3H).

175D. (2-(2-Phenylpropan-2-yl)thiazol-4-yl)methanol

To a solution of ethyl 2-(2-phenylpropan-2-yl)thiazole-4-carboxylate(0.515 g, 1.870 mmol) in THF (9 mL) was added LiBH₄ (0.081 g, 3.74mmol), followed by MeOH (0.151 mL, 3.74 mmol). The reaction mixture wassubsequently stirred at room temperature for 16 h and then quenched bydropwise addition of saturated aqueous NH₄Cl. The resulting mixture wasextracted with ethyl acetate, after which the organic phase was washedwith brine, dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by flash chromatography using a gradient of 0 to100% EtOAc in hexanes to give(2-(2-phenylpropan-2-yl)thiazol-4-yl)methanol (0.350 g, 80%) as a clear,colorless oil: LC (Method F): 1.528 min. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 7.35-7.26 (m, 5H), 7.22 (m, 1H), 5.26 (t, J=5.7 Hz, 1H), 4.53 (dd,J=0.8, 5.5 Hz, 2H), 1.76 (s, 6H).

Example 1752-Methoxy-6-(6-methoxy-4-((2-(2-phenylpropan-2-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.105 g, 0.330 mmol) and(2-(2-phenylpropan-2-yl)thiazol-4-yl)methanol (0.077 g, 0.330 mmol) indry THF (8 mL) was added tri-n-butylphosphine (0.214 mL, 0.825 mmol),followed by a solution of ADDP (0.208 g, 0.825 mmol) in THF (2 mL) addeddropwise over 30 min via syringe pump. After stirring for another 30min, the reaction mixture was partitioned between EtOAc and saturatedaqueous NaHCO₃. The organic phase was separated, washed with brine,dried (MgSO₄), filtered and concentrated to dryness. The residue waspurified by column chromatography using DCM-EtOAc as eluent to give thetitle compound (0.097 g, 0.182 mmol, 55.2%) as a beige solid. LC (MethodA): 2.536 min. HRMS(ESI): calcd for C₂₇H₂₅N₄O₄S₂ [M+H]⁺ m/z 533.1317,found 533.1336. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H), 7.69 (s,1H), 7.37-7.29 (m, 4H), 7.23 (m, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 6.62(d, J=2.0 Hz, 1H), 5.28 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 1.80 (s,6H).

Example 1766-(4-((2-(2-(4-Chlorophenyl)propan-2-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

176A. (2-(2-(4-Chlorophenyl)propan-2-yl)thiazol-4-yl)methanol

The alcohol was prepared according to the method described in Example175 above. LC (Method A): 2.032 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:7.36 (m, 4H), 7.29 (s, 1H), 5.27 (t, J=5.5 Hz, 1H), 4.53 (d, J=4.7 Hz,2H), 1.75 (s, 6H).

Example 1766-(4-((2-(2-(4-Chlorophenyl)propan-2-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 175 above and was isolated as a solid. LC (Method A): 2.588 min.HRMS(ESI): calcd for C₂₇H₂₄ClN₄O₄S₂ [M+H]⁺ m/z 567.0928, found 567.0937.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.37 (s, 1H) 7.70 (s, 1H), 7.37 (s,4H), 6.98 (s, 1H), 6.83 (d, J=0.8 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 5.28(s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 1.78 (s, 6H).

Example 1772-Methoxy-6-(6-methoxy-4-((2-(1-(pyridin-3-yl)cyclobutyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

177A. 1-(Pyridin-3-yl)cyclobutanecarbonitrile

To a solution of 2-(pyridin-3-yl)acetonitrile (0.903 mL, 8.46 mmol) indry THF (10 mL) was added 17 M sodium hydroxide (14.94 mL, 254 mmol) andtetrabutylammonium hydrogen sulfate (0.287 g, 0.846 mmol), followed bydropwise addition of 1,3-dibromopropane (0.902 mL, 8.89 mmol). Theresulting mixture was heated to reflux for 4 h and then it was allowedto cool and the aqueous phase was carefully decanted. The organic phasewas diluted with EtOAc, washed with water and brine, dried over MgSO₄,filtered and concentrated to dryness. The residue was purified by flashcolumn using a gradient of 0 to 10% MeOH: NH₄OH (9:1) in DCM to give1-(pyridin-3-yl)cyclobutanecarbonitrile (0.659 g, 49.2%) as a yellowoil. LC (Method A): 0.746 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.71(dd, J=0.8, 2.7 Hz, 1H), 8.57 (dd, J=1.6, 4.7 Hz, 1H), 7.92 (m, 1H),7.48 (ddd, J=0.8, 4.7, 7.8 Hz, 1H), 2.81-2.74 (m, 2H), 2.72-2.64 (m,2H), 2.30 (m, 1H), 2.04 (m, 1H).

177B. 1-(Pyridin-3-yl)cyclobutanecarboxamide

A mixture of 1-(pyridin-3-yl)cyclobutanecarbonitrile (0.659 g, 4.17mmol) and concentrated H₂SO₄ (4 mL) was stirred at ambient temperaturefor 16 h. The reaction mixture was then carefully poured onto crushedice and the mixture was basified with solid NaHCO₃ until gas evolutionceased. The mixture was then extracted with EtOAc and the organic phasewas separated, dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by flash column using 0 to 10% MeOH:NH₄OH (9:1) inDCM as eluent to give 1-(pyridin-3-yl)cyclobutanecarboxamide (0.283 g,34.7% yield) as a beige solid. LCMS (APCI): calcd for C₁₀H₁₃N₂O [M+H]⁺m/z 177.10, found 177.20. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.55 (dd,J=0.8, 2.7 Hz, 1H), 8.43 (m, 1H), 7.70 (m, 1H), 7.35 (ddd, J=0.8, 4.7,8.2 Hz, 1H), 7.28 (br s, 1H), 6.96 (br s, 1H), 2.75-2.66 (m, 2H),2.40-2.33 (m, 2H), 1.88-1.72 (m, 2H).

177C. 1-(Pyridin-3-yl)cyclobutanecarbothioamide

To a stirred solution of 1-(pyridin-3-yl)cyclobutanecarboxamide (0.283g, 1.445 mmol) in THF (5 mL) was added Lawesson's reagent (0.292 g,0.723 mmol) and the mixture was heated to reflux for 6 h. The cooledmixture was then concentrated to near dryness and the concentrate waspartitioned between EtOAc-saturated aqueous NaHCO₃. The organic phasewas separated, dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by column chromatography, using 0 to 10% MeOH:NH₄OH(9:1) in DCM as eluent to give 1-(pyridin-3-yl)cyclobutanecarbothioamide(0.208 g, 74.8%) as a white solid. LC (Method A): 0.929 min. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 9.54 (br s, 1H), 9.09 (br s, 1H), 8.73 (dd,J=0.8, 2.3 Hz 1H), 8.44 (dd, J=1.6, 4.7 Hz, 1H), 7.90 (m, 1H), 7.36(ddd, J=0.8, 4.7, 7.8 Hz, 1H), 2.87-2.80 (m, 2H), 2.59-2.52 (m, 2H),1.73-1.60 (m, 2H).

177D. Ethyl 2-(1-(pyridin-3-yl)cyclobutyl)thiazole-4-carboxylate

To a suspension of 1-(pyridin-3-yl)cyclobutanecarbothioamide (0.200 g,1.040 mmol) in ethanol (2 mL) at 0° C. was added dropwise a solution ofethyl 3-bromo-2-oxopropanoate (0.124 mL, 0.988 mmol) in ethanol (2 mL).The ice bath was then removed and the reaction mixture was stirred atambient temperature for 24 h, before being partitioned between EtOAc andsaturated aqueous NaHCO₃. The organic phase was separated, dried(MgSO₄), filtered and concentrated to dryness. The residue was purifiedby flash column using 0-10% MeOH:NH₄OH (9:1) in DCM to give ethyl2-(1-(pyridin-3-yl)cyclobutyl)thiazole-4-carboxylate (0.169 g, 53.0%yield) as a light yellow oil. LC (Method A): 1.456 min. LCMS (APCI):calcd for C₁₅H₁₇N₂O₂S [M+H]⁺ m/z 289.10, found 289.20.

177E. (2-(1-(Pyridin-3-yl)cyclobutyl)thiazol-4-yl)methanol

To a stirred solution of ethyl2-(1-(pyridin-3-yl)cyclobutyl)thiazole-4-carboxylate (0.169 g, 0.586mmol) in THF (3 mL) at ambient temperature was added LiBH₄ (0.027 g,1.232 mmol) followed by MeOH (0.050 mL, 1.232). The reaction mixture wasstirred for 16 h and then it was quenched by the addition of saturatedaqueous NH₄Cl. The resulting mixture was extracted with ethyl acetateand the organic phase was dried (MgSO₄), filtered and concentrated todryness. The residue was purified by flash column using a gradient of0-10% MeOH:NH₄OH (9:1) in DCM as eluent to give(2-(1-(pyridin-3-yl)cyclobutyl)thiazol-4-yl)methanol (0.053 g, 34.9%) asa clear, colorless oil. LC (Method A): 1.607 min. LCMS (APCI): calcd forC₁₃H₁₅N₂OS [M+H]⁺ m/z 247.09, found 247.20.

Example 1772-Methoxy-6-(6-methoxy-4-((2-(1-(pyridin-3-yl)cyclobutyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 175 above and was isolated as a solid. LC (Method A): 2.324 min.HRMS(ESI): calcd for C₂₇H₂₄N₅O₄S₂ [M+H]⁺ m/z 546.1270, found 546.1251.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.51 (d, J=5.5 Hz, 1H), 8.48 (m, 1H),8.36 (s, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.78 (s, 1H), 7.72 (dd, J=5.7, 8.0Hz, 1H), 7.18 (br s, 1H), 6.99 (d, J=0.8 Hz, 1H), 6.83 (dd, J=0.8, 1.6Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.27 (s, 2H), 4.36 (t, J=5.1 Hz, 1H),4.20 (s, 3H), 3.80 (s, 3H), 3.44 (m, 2H), 2.92-2.81 (m, 4H), 2.20-2.13(m, 1H), 2.02-1.92 (m, 1H).

Example 1782-Methoxy-6-(6-methoxy-4-((2-(1-(pyrimidin-5-yl)vinyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

178A. 1-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)ethanone

A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole(Example 37B, 2.00 g, 6.49 mmol) in dry THF (32 mL) was cooled at −78°C. under N₂ and then n-butyllithium (1.45 M in hexanes, 4.92 mL, 7.14mmol) was added dropwise. The resulting mixture was stirred for 35 minto give a pale brown solution. To this mixture was slowly added asolution of N,N-dimethylacetamide (0.608 mL, 6.49 mmol) in dry THF (8mL) and the mixture was stirred at −78° C. for 2 h to give a light brownsolution. The reaction was then quenched by the addition of saturatedaqueous NH₄Cl, the cooling bath was removed and the mixture waspartitioned with EtOAc-water. The organic phase was separated, washed(brine), dried (MgSO₄) and evaporated to give a pale yellow oil. Thisoil was purified by column chromatography using a gradient of 0 to 10%ether in hexanes as to give1-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)ethanone (1.07g, 60.8% yield) as a yellow oil. LC (Method A): 2.368 min. LCMS (APCI):calcd for C₁₂H₂₂NO₂SSi [M+H]⁺ m/z 272.11, found 272.20.

178B. 1-(4-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)vinyltrifluoromethanesulfonate

To a stirred solution of1-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)ethanone (1.068g, 3.93 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)-methanesulfonamide(1.546 g, 4.33 mmol) in THF (27 mL) at −78° C. was added KHMDS (1.1 M inTHF, 4.32 mL, 3.93 mmol) dropwise over 20 min. The reaction mixture wasthen allowed to warm to −20° C. and stirred at the same temperature for2 h, before being quenched with saturated aqueous NH₄Cl and extractedwith EtOAc. The organic phase was washed with brine, dried (MgSO₄),filtered and concentrated to dryness. The residue was purified by flashchromatography using a gradient of 0 to 10% diethyl ether in hexanes togive 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)vinyltrifluoromethanesulfonate (0.432 g, 27.2% yield) as a clear, colorlessoil. LC (Method A): 2.484 min. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 7.69 (s,1H), 6.31 (d, J=5.1 Hz, 1H), 5.84 (d, J=5.1 Hz, 1H), 4.78 (d, J=0.8 Hz,2H), 0.89 (s, 9H), 0.09 (s, 6H).

178C.4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(1-(pyrimidin-5-yl)vinyl)thiazole

To a mixture of1-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)vinyltrifluoromethanesulfonate (0.272 g, 0.506 mmol) andpyrimidin-5-ylboronic acid (0.094 g, 0.758 mmol) in toluene (8 mL) andethanol (1.5 mL) was added 2 M sodium carbonate (0.303 mL, 0.607 mmol)and the mixture was degassed with a stream of nitrogen bubbles for 5min. To this mixture was then added PdCl₂(dppf).CH₂Cl₂ (0.025 g, 0.030mmol), the vessel was sealed and the mixture was heated at 90° C. for 3h. The cooled mixture was partitioned with saturated aqueous NaHCO₃-DCMand the organic phase was separated, washed with brine, dried (MgSO₄),filtered and concentrated. The residue was purified by flash columnusing DCM-EtOAc as eluent to give4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(1-(pyrimidin-5-yl)vinyl)thiazole(0.103 g, 0.309 mmol, 61.1% yield) as a yellow oil. LC (Method A): 2.358min. LCMS (APCI): calcd for C₁₆H₂₄N₃OSSi [M+H]⁺ m/z 334.14, found334.20.

178D. (2-(1-(Pyrimidin-5-yl)vinyl)thiazol-4-yl)methanol

To a stirred solution of4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(1-(pyrimidin-5-yl)vinyl)thiazole(0.103 g, 0.309 mmol) in THF (2 mL) at ambient temperature was addedtriethylamine trihydrofluoride (0.251 mL, 1.544 mmol) and the mixturewas stirred for 16 h. The resulting mixture was partitioned withEtOAc-saturated aqueous NaHCO₃ and the organic phase was separated,dried (MgSO₄), filtered and evaporated to dryness. The residue waspurified flash column chromatography using hexanes-ethyl acetate aseluent to give (2-(1-(pyrimidin-5-yl)vinyl)thiazol-4-yl)methanol (0.017g, 0.078 mmol, 25.1%) as a clear, colorless oil. LC (Method A): 1.242min. LCMS (APCI): calcd for C₁₀H₁₀N₃OS [M+H]⁺ m/z 220.05, found 220.20.

Example 1782-Methoxy-6-(6-methoxy-4-((2-(1-(pyrimidin-5-yl)vinyl)thiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a suspension of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1H, 0.0246 g, 0.078 mmol) and(2-(1-(pyrimidin-5-yl)vinyl)thiazol-4-yl)methanol (0.017 g, 0.078 mmol)in dry THF (8 mL) was added tri-n-butylphosphine (0.050 mL, 0.194 mmol),followed by a solution of ADDP (0.049 g, 0.194 mmol) in THF (2 mL) addeddropwise over 30 min via syringe pump. After stirring for another 30min, the reaction mixture was partitioned with EtOAc-saturated aqueousNaHCO₃ and the organic phase was separated, washed with brine, dried(MgSO₄), filtered and concentrated to dryness. The residue was purifiedby flash column using DCM-EtOAc as eluent to give the impure product.This material was rechromatographed using hexanes-EtOAc as eluent togive the pure product as a white solid which was subsequentlylyophilized from acetonitrile-water to give the title compound (0.014 g,0.024 mmol, 30.6%) as an amorphous white solid. LC (Method A): 2.288min. HRMS(ESI): calcd for C₂₄H₁₉N₆O₄S₂ [M+H]⁺ m/z 519.0904, found519.0902. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 9.21 (s, 1H), 8.99 (s, 2H),8.36 (s, 1H), 7.92 (s, 1H), 7.00 (d, J=0.8 Hz, 1H), 6.83 (m, 1H), 6.61(d, J=2.0 Hz, 1H), 6.28 (s, 1H), 6.00 (s, 1H), 5.31 (s, 2H), 4.20 (s,3H), 3.79 (s, 3H).

Example 1796-(6-Fluoro-4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

179A. 4-Fluoro-2-hydroxy-6-methoxybenzaldehyde and2-fluoro-6-hydroxy-4-methoxybenzaldehyde

A 1:5 mixture of 4-fluoro-2,6-dimethoxybenzaldehyde and2-fluoro-4,6-dimethoxybenzaldehyde (Helvetica Chim. Acta, 81:1596-1607(1998), 1 g, 5.43 mmol) in 30 mL of dichloromethane was cooled down to0-5° C. To this mixture was added dropwise over 25 minutestribromoborane (7.33 mL, 7.33 mmol) in 10 mL of dichloromethane and thereaction was stirred at 0-5° C. for approx. 5-10 min. The mixture wasthen poured into ice, diluted down with dichloromethane and extractedtwice with dichloromethane. The combined organic layers were dried overMgSO₄, filtered and concentrated. The residue was purified on ISCOsilica gel column chromatography (40 g gold column using 90% hexanes and10% dichloromethane up to 80% hexanes with 10% dichloromethane and 10%ethyl acetate). Both isomers were collected at the same time to give thetitle materials (0.720 g, 78%) as a white crystalline solid.2-Fluoro-6-hydroxy-4-methoxybenzaldehyde (major isomer, undesired)—¹HNMR (400 MHz, CDCl₃) δ ppm: 11.91 (s, 1H), 10.05 (s, 1H), 6.17-6.25 (m,1H), 3.86 (s, 3H). 4-Fluoro-2-hydroxy-6-methoxybenzaldehyde (minorisomer, desired)—¹H NMR (400 MHz, CDCl₃) δ ppm: 12.23-12.42 (m, 1H),10.22 (s, 1H), 6.23-6.27 (m, 1H), 6.13 (dd, J=10.96, 2.35 Hz, 1H), 3.90(s, 3H).

179B. 1-(6-Fluoro-4-methoxybenzofuran-2-yl)ethanone

To a solution of a mixture of 4-fluoro-2-hydroxy-6-methoxybenzaldehydeand 2-fluoro-6-hydroxy-4-methoxybenzaldehyde (4.63 g, 27.2 mmol) inacetonitrile (49.7 mL, 952 mmol) was added potassium iodide (0.903 g,5.44 mmol), cesium carbonate (9.75 g, 29.9 mmol) and1-chloropropan-2-one (2.395 mL, 28.6 mmol). The mixture was stirred atr.t. for 2 h, was treated with 0.1 eq of cesium carbonate and heated to60° C. for 1 h and 80° C. for another hour. The reaction was leftovernight at r.t., then filtered over a small pad of silica and rinsedwith ethyl acetate (approx 500 mL). The residue obtained afterconcentration was purified by silica gel chromatography (ISCO, 120 g ofsilica with 100% toluene using UV at 315 nm, then polarity was increasedover time up to 10% ethyl acetate). The fractions were evaporated togive a 7:1 mixture of the desired/undesired isomers which wasrecrystallized overnight with ethyl acetate. The title material wasobtained (0.216 g, 3.8%) as colorless crystals. LC (Method B): 1.928min. LCMS (APCI) calcd for C₁₁H₁₀FO₃ [M+H]⁺ m/z 209.06, found 209.1. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 7.55-7.61 (m, 1H), 6.78-6.99 (m, 1H),6.46-6.53 (m, 1H), 3.96 (s, 3H), 2.55-2.60 (m, 3H).

179C. 1-(6-Fluoro-4-hydroxybenzofuran-2-yl)ethanone

To a stirred solution of 1-(4,6-dimethoxybenzofuran-2-yl)ethanone (0.216g, 1.038 mmol) in chlorobenzene (3.69 mL, 36.3 mmol) was added aluminumtrichloride (0.277 g, 2.075 mmol). After heating for 3 h at 85° C., themixture was quenched with ice and 1.0N HCl, and extracted with ethylacetate (4×). The combined organic layers were dried over anhydrousmagnesium sulphate, filtered and concentrated. The residue was purifiedon silica gel chromatography (BIOTAGE® 24 g, eluting with a gradient ofhexanes and ethyl acetate) to give the title material (0.191 g, 95%) asa white solid. LC (Method B): 1.794 min. LCMS (APCI) calcd for C₁₀H₈FO₃[M+H]⁺ m/z 195.05, found 195.9. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.58 (s,1H), 6.87-6.93 (m, 1H), 6.46-6.53 (m, 1H), 5.62 (s, 1H), 2.60 (s, 3H).

179D.1-(6-Fluoro-4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone

Benzene was added to 1-(6-fluoro-4-hydroxybenzofuran-2-yl)ethanone(0.178 g, 0.917 mmol) and the mixture was sonicated for 30 sec. andconcentrated in vacuo to remove traces of water in the startingmaterial. Triphenylphosphine (373 mgs, 1.421 mmol) was added and themixture was dried on high vacuum for 10 min.(2-Phenylthiazol-4-yl)methanol (Example 3B, 0.175 g, 0.917 mmol) and THF(15 mL) were added and the mixture was sonicated/heated for 5 min.Diisopropyl azodicarboxylate (275 μL, 1.412 mmol) in THF (2 mL) wasadded dropwise over 1 h and the resulting yellow solution was sonicatedfor 15 min. and stirred overnight at r.t. The mixture was diluted indichloromethane, washed with saturated. NaHCO₃, brine, dried over MgSO₄and concentrated. The residue was purified on silica gel chromatography(ISCO 24 g gold column, using 5% ethyl acetate in hexanes to 40% (10%increments)) to give the title material (0.132 g, 32%) as a white solid.LC (Method B): 2.613 min. LCMS (APCI) calcd for C₂₀H₁₅FNO₃S [M+H]⁺ m/z368.07, found 368.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.94-8.02 (m, 2H),7.62-7.67 (m, 1H), 7.44-7.51 (m, 3H), 7.38 (s, 1H), 6.91-6.96 (m, 1H),6.64-6.72 (m, 1H), 5.39 (d, J=0.78 Hz, 2H), 2.58 (s, 3H).

179E.2-Bromo-1-(6-fluoro-4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone

To a suspension of1-(6-fluoro-4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone(0.132 g, 0.359 mmol) in ethyl acetate (5 mL) was added copper(II)bromide (160 mgs, 0.719 mmol) and the mixture was heated to 80° C. for48 h. The solid was filtered off and rinsed with cold EtOAc. The solidwas purified on silica gel chromatography (ISCO 12 g withdichloromethane and ethyl acetate (95:5)) and provided the titlematerial (0.055 g, 34%) as an off-white solid. LC (Method B): 2.424 min.LCMS (APCI) calcd for C₂₀H₁₄BrFNO₃S [M+H]⁺ m/z 445.99, found 446.0.

179F.2-Bromo-6-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 2-5 mL microwave pressure vial was added2-bromo-1-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone(0.035 g, 0.078 mmol) in propan-2-ol (2 mL) followed by5-bromo-1,3,4-thiadiazol-2-amine (16.2 mgs, 0.09 mmol). The reaction washeated to 80° C. overnight and to 150° C. for 1 h in microwave oven. Thereaction mixture was then poured into a mixture of dichloromethane (8mL) and saturated NaHCO₃ (2 mL) and this was extracted twice withdichloromethane. The organic extracts were dried over MgSO₄, filteredand concentrated. The residue was purified by silica gel chromatography(ISCO 12 g gold column using 0 to 2% ethyl acetate in dichloromethane)to give the title material (0.018 g, 43%) as a yellowish solid. LC(Method B): 2.754 min. LCMS (APCI) calcd for C₂₂H₁₃BrFN₄O₂S₂ [M+H]⁺ m/z526.96, found 527.0.

Example 1796-(6-Fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

2-Bromo-6-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(0.017 g, 0.032 mmol) was dissolved in dichloromethane (1.3 mL) (someheat and sonication were required). Methanol was then added (0.3 mL)followed by sodium methoxide (14.74 μL, 0.064 mmol) in one shot. Thereaction was stirred at r.t. for 25 min., then quenched with 1.0 N HCland stirred until the reaction color changes to yellow. Saturatedaqueous NaHCO₃ was then added and this was extracted withdichloromethane (4×). The combined organic layers were dried over MgSO₄,filtered and concentrated. The residue was purified by silica gel columnchromatography (BIOTAGE® 12 g column using 0 to 5% ethyl acetate indichloromethane) to give the title material (0.010 g, 64%) as ayellowish solid. LC (Method A): 2.488 min. HRMS(ESI) calcd forC₂₃H₁₅FN₄O₃S₂ [M+H]⁺ m/z 479.0570, found 479.0661. ¹H NMR (CDCl₃, 400MHz) δ ppm: 7.94-8.03 (m, 2H), 7.89 (s, 1H), 7.43-7.53 (m, 3H), 7.39 (s,1H), 7.19 (s, 1H), 6.85-6.94 (m, 1H), 6.59-6.68 (m, 1H), 5.40 (s, 2H),4.23 (s, 3H).

Example 180N-(2-Cyanoethyl)-N-ethyl-4-(4-(((6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzamide

180A. 1-(4-(Benzyloxy)-6-fluorobenzofuran-2-yl)ethanone

A solution of 1-(6-fluoro-4-hydroxybenzofuran-2-yl)ethanone (Example179C, 1.00 g, 5.15 mmol) in N,N-dimethylformamide (10 mL) was treatedwith anhydrous potassium carbonate (0.747 g, 5.41 mmol), followed bybenzyl bromide (0.735 mL, 6.18 mmol) added dropwise over 5 min. Theresulting heterogeneous mixture was sonicated for 1 h and the resultingsuspension was then filtered and the filter-cake washed withN,N-dimethylformamide. The combined filtrate was evaporated to drynessand the residue was partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate. The organic phase was separated, washed withbrine, dried over anhydrous magnesium sulfate and concentrated in vacuo.The residue obtained was chromatographed on silica gel (ISCO, elutiongradient of dichloromethane in hexane) to give 1.33 g (91%) of the titlematerial as a white solid. LC (Method A): 2.334 min. HRMS(ESI): calcdfor C₁₇H₁₄FO₃ [M+H]⁺ m/z 285.0927; found 285.0927. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.59 (s, 1H), 7.33-7.49 (m, 5H), 6.76-6.94 (m, 1H),6.51-6.58 (m, 1H), 5.16 (s, 2H), 2.54 (s, 3H).

180B. 1-(4-(Benzyloxy)-6-fluorobenzofuran-2-yl)-2-bromoethanone

To a flask equipped with a magnetic stirring bar and purged with anitrogen atmosphere was added dry THF (35 mL) followed by lithiumbis(trimethylsilyl)amide (1 M in THF, 6.30 mL, 6.30 mmol). The mixturewas cooled to −78° C. and chlorotrimethylsilane (0.771 mL, 6.04 mmol)was added dropwise over 2 min. After 5 min, a solution of1-(4-(benzyloxy)-6-fluorobenzofuran-2-yl)ethanone (1.492 g, 5.25 mmol)in dry THF (14 mL) was added dropwise over 10 min and the resultingmixture was stirred at −78° C. for 30 min. The cooling bath was thenremoved and the mixture was allowed to warm to ca. 10° C. over 20 min.The reaction mixture was then quenched by addition to a cold mixture ofethyl acetate (300 mL), saturated aqueous sodium bicarbonate (40 mL) andice. The organic phase was rapidly separated, dried over anhydrousmagnesium sulfate and evaporated in vacuo to give the silyl enol etheras a clear oil. This oil was co-evaporated with toluene (10 mL, 2 mbar)before being taken up in dry tetrahydrofuran (35 mL). The mixture wascooled to −35° C. under nitrogen and treated with solid sodiumbicarbonate (30 mg), followed by N-bromosuccinimide (0.981 g, 5.51mmol), added in small portions over 10 min. The reaction mixture wasallowed to warm to 5° C. over 3.5 h and then it was quenched by additionof ethyl acetate (400 mL) and saturated aqueous sodium bicarbonate (40mL). The organic phase was separated, washed with brine, dried overanhydrous magnesium sulfate and evaporated to give a white solid.Chromatography on silica gel (ISCO, elution gradient of dichloromethanein hexane) gave 1.509 g (79%) of the title material as a yellow solid.LC (Method A): 2.282 min. HRMS(ESI): calcd for C₁₇H₁₃BrFO₃ [M+H]⁺ m/z363.0032; found 363.004. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.75 (d, J=0.78Hz, 1H), 7.35-7.51 (m, 5H), 6.91 (m, 1H), 6.58 (dd, J=11.35, 1.96 Hz,1H), 5.19 (s, 2H), 4.37 (s, 2H).

180C.6-(4-(Benzyloxy)-6-fluorobenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole

A mixture of 1-(4-(benzyloxy)-6-fluorobenzofuran-2-yl)-2-bromoethanone(1.07 g, 2.95 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.610 g, 3.39mmol) in isopropanol (80 mL) was heated in a sealed pressure flask at80° C. for 18 h. The resulting heterogeneous mixture was then heated ina microwave reactor at 150° C. for 30 min. The cooled reaction mixturewas partitioned with dichloromethane-saturated aqueous sodiumbicarbonate and the organic phase was separated, washed with brine,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresidue obtained was chromatographed on silica gel (ISCO, elutiongradient of ethyl acetate in dichloromethane) to give 0.740 g (57%) ofthe title material as a solid. LC (Method A): 2.456 min. HRMS(ESI):calcd for C₁₉H₁₂BrFN₃O₂S [M+H]⁺ m/z 443.9818; found 443.9834. ¹H NMR(400 MHz, CDCl₃) δ ppm: 8.09 (s, 1H), 7.32-7.54 (m, 5H), 7.21 (s, 1H),6.86-6.91 (m, 1H), 6.52-6.59 (m, 1H), 5.21 (s, 2H).

180D.6-(4-(Benzyloxy)-6-fluorobenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A suspension of6-(4-(benzyloxy)-6-fluorobenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole(0.740 g, 1.666 mmol) in a mixture of dichloromethane (30 mL) andmethanol (10 mL) was treated at 22° C. with sodium methoxide (25 wt % inMeOH, 1.01 mL, 4.45 mmol), added in one portion. After 30 min, the clearreaction mixture was quenched by the addition of 5 mL of 1 Nhydrochloric acid and the solvent was evaporated under reduced pressure.The residue was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate, and the organic phase was separated, washedwith brine, dried over anhydrous magnesium sulfate and evaporated invacuo. Chromatography of the residue on silica gel (ISCO, elutiongradient of ethyl acetate in dichloromethane) gave 0.480 g (82%) of thetitle compound as a white solid. LC (Method A): 2.477 min. HRMS(ESI):calcd for C₂₀H₁₅FN₃O₃S [M+H]⁺ m/z 396.0818; found 396.0862. ¹H NMR (400MHz, CDCl₃) δ ppm: 7.88 (s, 1H), 7.32-7.55 (m, 5H), 7.13 (s, 1H), 6.88(m, 1H), 6.54 (m, 1H), 5.20 (s, 2H), 4.22 (s, 3H).

180E.6-Fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol

A mixture of6-(4-(benzyloxy)-6-fluorobenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.480 g, 1.21 mmol) and pentamethylbenzene (1.26 g, 8.50 mmol) indichloromethane (75 mL) was cooled at −78° C. under nitrogen and thentreated with boron trichloride (1 M in DCM, 3.5 mL, 3.5 mmol), addeddropwise over 2 min. The resulting mixture was stirred at −78° C. for 40min and then it was quenched by the addition of saturated aqueous sodiumbicarbonate (45 mL). The cooling bath was removed and the resultingmixture was stirred at room temperature for 2 h. The resultingsuspension was filtered and the filter-cake was washed successively withwater and dichloromethane and then it was dried in vacuo (overphosphorous pentoxide) to give 0.363 g (98%) of title compound as a tansolid. LC (Method A): 2.096 min. HRMS(ESI): calcd for C₁₃H₉FN₃O₃S [M+H]⁺m/z 306.0349; found 306.0369. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.51 (brs, 1H), 8.41 (s, 1H), 7.07 (s, 1H), 6.90-6.99 (m, 1H), 6.42-6.52 (m,1H), 4.21 (s, 3H).

180F. tert-Butyl4-(4-(((6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoate

The title compound was prepared according to the general proceduredescribed in Example 36. LC (Method A): 2.689 min. HRMS(ESI): calcd forC₂₈H₂₄FN₄O₅S₂ [M+H]⁺ m/z 579.1172; found 579.1159. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.99-8.11 (m, 4H), 7.89 (s, 1H), 7.44 (s, 1H), 7.15 (s,1H), 6.88-6.94 (m, 1H), 6.63 (dd, J=11.35, 1.96 Hz, 1H), 5.42 (s, 2H),4.22 (s, 3H), 1.63 (s, 9H).

180G.4-(4-(((6-Fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoicacid

To a solution of tert-butyl4-(4-(((6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoate(0.345 g, 0.596 mmol) in dichloromethane (6 mL) was addedtrifluoroacetic acid (3 mL) and the homogenous yellowish mixture wasstirred at room temperature for 4 h. The volatiles were then evaporatedunder reduced pressure and the resulting solid residue was trituratedwith dichloromethane, filtered and dried in vacuo to give 0.272 g (87%)of the title compound as a beige solid. LC (Method A): 2.428 min.HRMS(ESI): calcd. for C₂₄H₁₆FN₄O₅S₂[M+H]⁺ m/z 523.0546; found 523.0541.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.46 (s, 1H), 8.00-8.13 (m, 5H), 7.18(d, J=9.00 Hz, 1H), 7.12 (m, 1H), 6.99-7.06 (m, 1H), 5.44 (s, 2H), 4.20(s, 3H).

Example 180N-(2-Cyanoethyl)-N-ethyl-4-(4-(((6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzamide

A solution of4-(4-(((6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoicacid (0.040 g, 0.077 mmol) in N,N-dimethylformamide (2 mL) was treatedwith diisopropylethylamine (0.067 mL, 0.383 mmol), followed by3-(ethylamino)propanenitrile (0.0083 g, 0.084 mmol). HATU (0.032 g,0.084 mmol) was then added and the reaction mixture was stirred at roomtemperature for 3 h. The volatiles were then evaporated in vacuo and theresidue was partitioned between chloroform and saturated aqueous sodiumbicarbonate. The organic phase was separated, washed with brine, driedover anhydrous sodium sulfate and evaporated in vacuo. Chromatography ofthe residue on silica gel (ISCO, elution gradient of ethyl acetate inchloroform) gave 0.034 g (74%) of the title compound as a white solid.LC (Method A): 2.374 min. HRMS(ESI): calcd for C₂₉H₂₄FN₆O₄S₂[M+H]⁺ m/z603.1285; found 603.1286. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.05 (m, 2H),7.89 (s, 1H), 7.52 (m, 2H), 7.43 (d, J=0.78 Hz, 1H), 7.15 (s, 1H), 6.91(d, J=8.61 Hz, 1H), 6.63 (dd, J=11.54, 1.76 Hz, 1H), 5.41 (s, 2H), 4.22(s, 3H), 3.74 (br s, 2H), 3.46 (br s, 2H), 2.87 (br s, 2H), 1.21 (br s,3H).

Example 1814-(4-(((6-Fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N-(2,2,2-trifluoroethyl)benzamide

The title compound was prepared according to the method described inExample 180 above. LC (Method A): 2.369 min. HRMS(ESI): calcd forC₂₆H₁₈F₄N₅O₄S₂[M+H]⁺ m/z 604.0736; found 604.0725. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 9.24 (t, J=6.26 Hz, 1H), 8.46 (s, 1H), 8.06-8.14 (m,2H), 7.98-8.06 (m, 3H), 7.18 (d, J=7.83 Hz, 1H), 7.12 (s, 1H), 7.03 (dd,J=12.13, 1.96 Hz, 1H), 5.44 (s, 2H), 4.20 (s, 3H), 4.04-4.17 (m, 2H).

Example 182N-(tert-Butyl)-4-(4-(((6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N-methylbenzamide

The title compound was prepared according to the method described inExample 180 above. LC (Method A): 2.391 min. HRMS(ESI): calcd. forC₂₉H₂₇FN₅O₄S₂[M+H]⁺ m/z 592.1489; found 592.1500. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.88-7.94 (m, 2H), 7.81 (s, 1H), 7.41-7.48 (m, 2H), 7.33(s, 1H), 7.07 (s, 1H), 6.83 (dd, J=8.61, 0.78 Hz, 1H), 6.55 (dd,J=11.35, 1.96 Hz, 1H), 5.32 (s, 2H), 4.14 (s, 3H), 2.82 (s, 3H), 1.46(s, 9H).

Example 183(4-(4-(((6-Fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)phenyl)(pyrrolidin-1-yl)methanone

The title compound was prepared according to the method described inExample 180 above. LC (Method A): 2.307 min. HRMS(ESI): calcd forC₂₈H₂₃FN₅O₄S₂[M+H]⁺ m/z 576.1176; found 576.1159. ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.02 (m, 2H), 7.89 (s, 1H), 7.63 (m, 2H), 7.42 (s, 1H),7.16 (s, 1H), 6.91 (d, J=8.61 Hz, 1H), 6.63 (dd, J=11.35, 1.96 Hz, 1H),5.41 (s, 2H), 4.22 (s, 3H), 3.68 (t, J=6.85 Hz, 2H), 3.47 (t, J=6.46 Hz,2H), 1.84-2.05 (m, 4H).

Example 184N-(Cyanomethyl)-4-(4-(((6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N-methylbenzamide

The title compound was prepared according to the method described inExample 180 above. LC (Method A): 2.274 min. HRMS(ESI): calcd forC₂₇H₂₀FN₆O₄S₂[M+H]⁺ m/z 575.0972; found 575.0963. ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.07 (m, 2H), 7.89 (s, 1H), 7.58 (m, 2H), 7.45 (s, 1H),7.15 (s, 1H), 6.91 (dd, J=8.61, 0.78 Hz, 1H), 6.62 (dd, J=11.35, 1.96Hz, 1H), 5.41 (s, 2H), 4.49 (br s, 2H), 4.22 (s, 3H), 3.20 (s, 3H).

Example 1854-(4-(((6-Fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

The title compound was prepared from6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 180E) and4-(4-(hydroxymethyl)thiazol-2-yl)-N,N-dimethylbenzamide (Example 36B)according to the general method described in Example 36. LC (Method A):2.327 min. HRMS(ESI): calcd for C₂₆H₂₁FN₅O₄S₂ [M+H]⁺ m/z 550.1019;found: 550.0999. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.02 (m, 2H), 7.89 (s,1H), 7.53 (m, 2H), 7.42 (s, 1H), 7.15 (s, 1H), 6.91 (d, J=8.61 Hz, 1H),6.63 (d, J=11.35 Hz, 1H), 5.41 (s, 2H), 4.22 (s, 3H), 3.15 (br s, 3H),3.02 (br s, 3H).

Example 1864-(4-(((6-Fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-methylbenzamide

186A. tert-Butyl4-(4-(((6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)benzoate

The title compound was prepared from6-fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 180E) and tert-butyl4-(4-(hydroxymethyl)-5-methylthiazol-2-yl)benzoate (Example 45D)according to the general method described in Example 180F. LC (MethodA): 2.788 min. HRMS(ESI): calcd for C₂₉H₂₆FN₄O₅S₂ [M+H]⁺ m/z 593.1329;found 593.1318. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.02-8.07 (m, 2H),7.93-7.99 (m, 2H), 7.87 (s, 1H), 7.08 (s, 1H), 6.89 (dd, J=8.61, 0.78Hz, 1H), 6.73 (dd, J=11.74, 1.96 Hz, 1H), 5.34 (s, 2H), 4.21 (s, 3H),2.60 (s, 3H), 1.62 (s, 9H).

186B.4-(4-(((6-Fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)benzoicacid

The title compound was prepared according to the general deprotectionmethod described in Example 180G. LC (Method A): 2.436 min. HRMS(ESI):calcd for C₂₅H₁₅FN₄O₅S₂ [M+H]⁺ m/z 537.0703; found 537.0696. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 13.14 (br s, 1H), 8.46 (s, 1H), 7.99-8.08 (m, 4H),7.14-7.21 (m, 1H), 6.99-7.09 (m, 2H), 5.37 (s, 2H), 4.20 (s, 3H), 2.60(s, 3H).

Example 1864-(4-(((6-Fluoro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)-N-methylbenzamide

The title compound was prepared according to the general amide couplingmethod described in Example 180. LC (Method A): 2.389 min. HRMS(ESI):calcd for C₂₆H₂₀FN₅O₄S₂ [M+H]⁺ m/z 549.0941; found 550.1029. ¹H NMR (400MHz, CDCl₃) δ ppm: 7.98 (d, J=8.0 Hz, 2H), 7.87 (s, 1H), 7.83 (d, J=8.0Hz, 2H), 7.08 (s, 1H), 6.89 (d, J=8.61 Hz, 1H), 6.72 (dd, J=11.54, 1.76Hz, 1H), 6.15 (br s, 1H), 5.33 (s, 2H), 4.22 (s, 3H), 3.05 (d, J=5.09Hz, 3H), 2.59 (s, 3H).

Example 1876-(6-Chloro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

187A. 4-Chloro-2,6-dimethoxybenzaldehyde

A solution of 1-chloro-3,5-dimethoxybenzene (5 g, 29.0 mmol) and TMEDA(4.37 mL, 29.0 mmol) in diethyl ether (100 mL, 962 mmol) at −78° C.under N₂ atmosphere was charged with BuLi (19.91 mL, 31.9 mmol) dropwiseover a period of 30 minutes using a syringe pump. After stirring for 4hours at −78° C., DMF was added and the reaction mixture continued tostir for 1.5 hours after which 1N HCl (˜30 mL) was added (all at −78°C.). The reaction mixture was warmed to room temperature and extractedwithy ethyl acetate. The organic phase was dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by ISCO usinghexanes/EtOAc as eluent. Fractions containing the desired product wereconcentrated to dryness to give the title material (1.97 g, 9.82 mmol,33.9% yield) as a light yellow solid. LC (Method B): 1.924 min. LCMS(APCI) calcd for C₉H₁₀ClO₃ [M+H]⁺ m/z 201.03, found 201.0. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 10.28 (s, 1H), 6.87 (s, 2H), 3.86 (s, 6H).

187B. 4-Chloro-2-hydroxy-6-methoxybenzaldehyde

A stirred solution of 4-chloro-2,6-dimethoxybenzaldehyde (1.95 g, 9.72mmol) in DCM (20 mL, 311 mmol) at −78° C. was slowly added borontribromide (9.72 mL, 9.72 mmol). The reaction mixture was stirred at−78° C. for 10 minutes then warmed to r.t. and stirred for 1 hour whilemonitoring reaction progress by LCMS. Once all s.m. had been consumed,the reaction was quenched with water and extracted with DCM. The organicphase was washed with brine, dried (MgSO₄), filtered and concentrated todryness to give the title material (1.79 g, 9.59 mmol, 99% yield) as apurple solid. LC (Method B): 2.199 min. LCMS (APCI) calcd for C₈H₈ClO₃[M+H]⁺ m/z 187.02, found 187.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 11.89 (s,1H), 10.20 (s, 1H), 6.75 (t, J=2.0 Hz, 1H), 6.66 (m, 1H), 3.91 (s, 1H).

187C. 1-(6-Chloro-4-methoxybenzofuran-2-yl)ethanone

A stirred solution of 4-chloro-2-hydroxy-6-methoxybenzaldehyde (1.79 g,9.59 mmol) in N,N-dimethylformamide (15 mL, 9.59 mmol) was charged withcesium carbonate (3.75 g, 11.51 mmol) and 1-chloropropan-2-one (0.975mL, 11.51 mmol). The reaction mixture was heated in a sealable vessel at65° C. for 7 hours, was filtered over a Whatman filter paper to removeinsolubles rinsing with DCM then washed with sat. NaHCO₃. The organicphase was dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by ISCO using hexanes/EtOAc as eluent. Fractionscontaining the desired product were concentrated to give the titlematerial (1.43 g, 6.37 mmol, 66% yield) as a light yellow solid. LC(Method A): 1.952 min. LCMS (APCI) calcd for C₁₁H₁₀ClO₃ [M+H]⁺ m/z225.03, found 225.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.94 (d, J=0.8 Hz,1H), 7.49 (dd, J=0.8, 1.6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 3.97 (s, 3H).

187D. 1-(6-Chloro-4-hydroxybenzofuran-2-yl)ethanone

To a stirred solution of 1-(6-chloro-4-methoxybenzofuran-2-yl)ethanone(1.43 g, 6.37 mmol) in chlorobenzene (15 mL, 148 mmol) was addedaluminum chloride (3.40 g, 25.5 mmol) in portions over a period of 10minutes. The reaction vessel was then sealed and heated at 100° C. for40 minutes, then cool to r.t. and poured onto crushed ice (rinsedstirring bar with EtOAc). This was stirred for 30 minutes, thenextracted with ethyl acetate. The organic phase was dried (MgSO₄),filtered and concentrated to dryness. The residue was purified by ISCOusing hexanes/EtOAc as eluent. Fractions containing the desired productwere concentrated to give the title material (1.18 g, 5.60 mmol, 88%yield) as a light brown solid. LC (Method A): 1.783 min. LCMS (APCI)calcd for C₁₀H₈ClO₃ [M+H]⁺ m/z 211.02, found 211.0. ¹H NMR (CDCl₃, 400MHz) δ ppm: 11.01 (s, 1H), 7.89 (s, 1H), 6.72 (s, 1H), 2.52 (s, 3H).

187E. 1-(4-(Benzyloxy)-6-chlorobenzofuran-2-yl)ethanone

A stirred solution of 1-(6-chloro-4-hydroxybenzofuran-2-yl)ethanone(1.18 g, 5.60 mmol) in dry DMF (10 mL, 129 mmol) at r.t. was chargedwith K₂CO₃ (0.774 g, 5.60 mmol) and DMF. The reaction mixture wasstirred for 1.5 hours then partitioned between ethyl acetate and water.The organic phase was washed with brine, dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by ISCO usinghexanes/EtOAc as eluent. Fractions containing the desired product wereconcentrated to give the title material (1.57 g, 5.22 mmol, 93% yield)as an amber colored oil. LC (Method B): 2.420 min. LCMS (APCI) calcd forC₁₇H₁₄ClO₃ [M+H]⁺ m/z 301.06, found 301.0. ¹H NMR (CDCl₃, 400 MHz) δppm: 8.00 (d, J=0.8 Hz, 1H), 7.53 (m, 3H), 7.44 (m, 2H), 7.38 (m, 1H),7.10 (d, J=1.6 Hz, 1H), 5.53 (s, 2H), 2.54 (s, 3H).

187F. 1-(4-(Benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoethanone

A flame dried 200 ml round-bottom flask equipped with a stirring bar andunder nitrogen atmosphere was charged with anhydrous THF (12 mL)followed by lithium bis(trimethylsilyl)amide (6.22 mL, 6.22 mmol). Themixture was cooled to −78° C. and treated with a solution of1-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)ethanone (1.56 g, 5.19 mmol) inTHF (6 ml+2 ml washing) added dropwise over 10 minutes via a syringepump. The resulting mixture was stirred at −78° C. for 45 minutes andwas then charged with trimethylchlorosilane (0.769 mL, 6.02 mmol) addeddropwise over 5 minutes by syringe pump then stirred for another 20minutes. The cooling bath was removed and the mixture was allowed towarm to +10° C. for 30 minutes. The reaction mixture was quenched with amixture of cold ethyl acetate (80 mL), sat. NaHCO₃ (12 mL) and ice. Theorganic phase was dried (MgSO₄), stirring for ˜5 minutes to remove alltraces of water), filtered and concentrated to dryness to give the silylenol ether as a yellow oil which was co-evaporated with toluene (4 mL).The silyl enol ether was dissolved in dry THF (20 mL), cooled to −30° C.(employing a cooling bath made from 1:1 CaCl₂: water using dry ice, bathstabilizes around −30 to −45° C.) and treated with NaHCO₃ (˜50 mgs)followed by N-bromosuccinimide (0.923 g, 5.19 mmol) added in smallportions over 15 minutes. The reaction mixture was allowed to warm to 0°C. over 2 hours (monitored by LCMS) and then quenched by addition ofethyl acetate (100 mL) and sat. NaHCO₃. The organic phase was washedwith brine, dried (MgSO₄) and evaporated to give an orange solid whichwas purified by ISCO using hexanes/EtOAc as eluent. Fractions containingthe desired product were concentrated to give the title material 1.48 g,3.51 mmol, 67.6% yield) as a yellow solid. LC (Method B): 2.528 min.LCMS (APCI) calcd for C₁₇H₁₃BrClO₃ [M+H]⁺ m/z 378.97, found 379.0.

187G.6-(4-(Benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole

A sealable vessel was charged with1-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoethanone (1.48 g, 3.51mmol), 5-bromo-1,3,4-thiadiazol-2-amine (0.632 g, 3.51 mmol) and IPA (25mL, 324 mmol). The reaction mixture was heated in an oil bath at 80° C.for 6 hours then heated in the microwave at 150° C. for 1 hour. Thereaction mixture was allowed to stand for 1 hour and the insolublematerial was filtered off and rinsed with MeOH to give the desiredproduct as a brown solid (1.19 g, 2.58 mmol, 73.6% yield). LC (MethodA): 2.549 min. LCMS (APCI) calcd for C₁₉H₁₂BrClN₃O₂S [M+H]⁺ m/z 459.95,found 460.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.74 (s, 1H), 7.55-7.50 (m,2H), 7.45-7.34 (m, 4H), 7.17 (d, J=0.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H),5.32 (s, 2H).

187H.6-(4-(Benzyloxy)-6-chlorobenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a stirred solution of6-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole(1.18 g, 2.56 mmol) in DCM (40 mL, 622 mmol) and methanol (10 mL, 247mmol) was added sodium methoxide (1.164 mL, 5.12 mmol). The reactionmixture was stirred at r.t. for 1 h 15 min while monitoring by TLC (7:3hexanes:EtOAc). The reaction mixture was quenched with 1N HCl andextracted with DCM. The organic phase was washed with brine, dried(MgSO₄), filtered and concentrated to dryness. The residue wastriturated with MeOH (sonication) and the solid material was filteredoff, rinsed with MeOH and sucked dry to give the desired compound as abrown solid (859 mg, 2.086 mmol, 81% yield). LC (Method A): 2.478 min.LCMS (APCI) calcd for C₂₀H₁₅ClN₃O₃S [M+H]⁺ m/z 412.05, found 412.0. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 8.50 (s, 1H), 7.52 (m, 2H), 7.43 (m, 2H),7.36 (m, 2H), 7.09 (d, J=0.8 Hz, 1H), 7.00 (d, J=1.6 Hz, 1H), 5.31 (s,2H), 4.21 (s, 3H).

187I.6-Chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol

A stirred solution of6-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.85 g, 2.064 mmol) and pentamethylbenzene (2.142 g, 14.45 mmol) in DCMunder N₂ atmosphere was cooled to −78° C. after which boron trichloride(5.16 mL, 5.16 mmol) was added dropwise over ˜4 minutes. The reactionwas monitored by TLC using 1:1 hexanes-EtOAc as eluent. The reactionmixture was stirred at −78° C. for 30 minutes after which a mixture ofwater (40 mL) and saturated NaHCO₃ (5 mL) was added (at −78° C.) and themixture was stirred until ambient temperature was obtained (removed fromcooling bath). The solid precipitate was filtered off and rinsed withdiethyl ether then allowed to dry overnight to give the title material(441 mgs, 1.371 mmol, 66.4% yield) as a beige solid. The filtrate wasextracted with DCM. The organic phase was washed with brine, dried(MgSO₄) and concentrated to dryness. The residue was purified by ISCOusing DCM/EtOAc as eluent. Fractions containing the desired product wereconcentrated to give the title material (25 mgs, 0.078 mmol, 3.77%yield) as a beige solid. LC (Method A): 2.167 min. LCMS (APCI) calcd forC₁₃H₉ClN₃O₃S [M+H]⁺ m/z 322.00, found 322.0. ¹H NMR (CDCl₃, 400 MHz) δppm: 10.50 (br. S, 1H), 8.45 (s, 1H), 7.17 (dd, J=0.8, 1.6 Hz, 1H), 7.09(d, J=0.8 Hz, 1H), 6.67 (d, J=2.0 Hz, 2H), 4.21 (s, 3H).

Example 1876-(6-Chloro-4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A flame-dried 100 mL round-bottom flask containing6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(0.025 g, 0.078 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B,37.2 mgs, 0.194 mmol) in dry THF (4 mL) was added tributylphosphine(0.050 mL, 0.194 mmol). The resulting solution was charged with asolution of ADDP (0.049 g, 0.194 mmol) in THF (1 mL) added dropwise over30 minutes via syringe pump. After stirring for 1.5 hours the reactionmixture was diluted with EtOAc then washed with 1N HCl, sat. NaHCO₃,water and brine. The organic phase was dried (MgSO₄) then concentratedto dryness. The residue was purified by ISCO using 0 to 10% diethylether in DCM. Fractions containing the desired product were concentratedto give the title material as a beige solid (0.020 g, 0.040 mmol, 52.0%yield). LC (Method A): 2.534 min. LCMS (APCI) calcd for C₂₃H₁₆ClN₄O₃S₂[M+H]⁺ m/z 495.03, found 495.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.49 (s,1H), 7.99-7.96 (m, 2H), 7.93 (s, 1H), 7.55-7.50 (m, 3H), 7.40 (dd,J=0.8, 1.6 Hz, 1H), 7.15 (dd, J=0.4, 1.6 Hz, 1H), 7.14 (d, J=0.8 Hz,1H), 5.43 (s, 2H), 4.21 (s, 3H).

Example 1886-(6-Chloro-4-((2-(4-chlorophenyl)thiazol-4-yl)methoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A suspension of6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1871, 0.030 g, 0.093 mmol) and2-(bromomethyl)-4-(4-chlorophenyl)thiazole (0.0404 g, 0.140 mmol) inN,N-dimethylformamide (3 mL) was maintained under vacuum (10 mbar) for 5min. The flask was then flushed with nitrogen and freshly powderedanhydrous potassium carbonate (0.105 g, 0.756 mmol) was added all atonce. The resulting mixture was stirred at room temperature for 16 h.The heterogeneous mixture was quenched with 1 N hydrochloric acid (1 mL)after which water and MeOH were added. The solid material was filteredoff and the filter-cake was rinsed with water, methanol and acetonitrileto give a beige solid. The solid material was dissolved in DCM with asmall amount of methanol, then adsorbed onto a silica gel pre-column andpurified by flash chromatography (0-100% EtOAc-dichloromethane). Theobtained product was lyophilized from acetonitrile-water to give thetitle compound as an amorphous beige solid (0.031 g, 0.059 mmol, 62.8%).LC (Method F): 2.714 min. HRMS(ESI): calcd for C₂₃H₁₅Cl₂N₄O₃S₂ [M+H]⁺m/z 528.9963, found 528.9954. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.47 (s,1H), 7.98 (m, 2H), 7.94 (s, 1H), 7.58 (m, 2H), 7.38 (s, 1H), 7.12 (d,J=0.8 Hz, 2H), 5.42 (s, 2H), 4.20 (s, 3H).

Example 1896-(6-Chloro-4-((2-(m-tolyl)thiazol-4-yl)methoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 188 above to give a solid. LC (Method F): 2.687 min. HRMS(ESI):calcd for C₂₄H₁₈ClN₄O₃S₂ [M+H]⁺ m/z 509.0509, found 509.0512. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 8.49 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.76(d, J=7.8 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.15(d, J=1.6 Hz, 1H), 7.14 (d, J=0.8 Hz, 1H), 5.42 (s, 2H), 4.20 (s, 3H),2.39 (s, 3H).

Example 190(6-(6-Chloro-4-((2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a solution of4-(bromomethyl)-2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazole (Example119C, 0.016 g, 0.057 mmol) in DMF (1.5 mL) was added6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1871, 0.017 g, 0.052 mmol), followed by freshly powderedpotassium carbonate (0.022 g, 0.156 mmol). The mixture was stirred in asealed vial at room temperature for 2 h and then it was diluted withwater and the resulting mixture was filtered and the filter-cake waswashed with saturated aqueous NH₄Cl and then with water. The wet residuewas taken up in DCM and the solution was washed (saturated aqueousNaHCO₃), dried (Na₂SO₄) and evaporated to give a gum. Flashchromatography (Isco/0-30% EtOAc-DCM) afforded6-(6-chloro-4-((2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.012 g, 44.4%) as a solid. LC (Method A): 2.483 min. HRMS(ESI): calcdfor C₂₂H₁₉ClFN₄O₄S₂ [M+H]⁺ m/z 521.052; found 521.053. ¹H NMR (400 MHz,DMSO-d₆): δ 8.46 (s, 1H), 7.94 (s, 1H), 7.36 (br s, 1H), 7.08 (d, J=1.57Hz, 1H), 7.07 (s, 1H), 5.35 (s, 2H), 4.17 (s, 3H), 3.81 (m, 2H), 3.67(dt, J=1.96, 10.96 Hz, 2H), 2.33-2.16 (m, 2H), 2.05 (m, 2H).

Example 1912-Methoxy-6-(4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

191A. 5-(Benzyloxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one

A solution of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (6.00g, 30.9 mmol) (Hadfield, A. et al., Synthetic Communications,24(7):1025-1028 (1994)) in N,N-dimethylformamide (35 mL) was treatedwith powdered anhydrous potassium carbonate (5.15 g, 37.26 mmol) addedall at once. The resulting mixture was stirred in vacuo for 10 min. andthen flushed with nitrogen. The reaction flask was placed in a waterbath (22° C.) and treated with benzyl bromide (5.55 g, 32.16 mmol) addeddropwise over 15 min. The resulting mixture was then stirred at 22° C.for 18 h. The solid formed was filtered and washed withN,N-dimethylformamide. The filtrate was evaporated in vacuo and theresidual oil was diluted with ethyl acetate (300 mL), washed with cold0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. Afterdrying over anhydrous magnesium sulfate, evaporation of the solvent gavea thick syrup. Chromatography on silica gel (4×13 cm, elutiontoluene-ethyl acetate 0-5%) gave 8.78 g (100% yield) of the titlematerial as a white solid. LC (Method A): 1.982 min. ¹H NMR (CDCl₃, 600MHz) δ ppm: 1.69 (s, 6H), 5.23 (s, 2H), 6.53 (d, J=8.2 Hz, 1H), 6.62 (d,J=8.4 Hz, 1H), 7.24-7.3 (m, 1H), 7.34-7.4 (m, 3 H), 7.52 (broad d, J=7.4Hz 2H).

191B. 2-(Benzyloxy)-6-hydroxybenzaldehyde

A solution of 5-(benzyloxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one(4.00 g, 14.07 mmol) in dichloromethane (80 mL) was cooled to −78° C.and treated with a solution of diisobutylaluminum hydride (6.00 g, 42.2mmol) in toluene (40 mL) added dropwise over 20 min. The resultingmixture was then stirred at −78° C. for 3 h. The reaction mixture wasquenched by the careful addition of methanol (5 mL) added dropwise over15 min, followed by 4 N hydrochloric acid (20 mL) added dropwise over 15min. The cooling bath was then removed and an additional 80 mL of 4Nhydrochloric acid was added over 10 min and the mixture was stirredvigorously at 22° C. for 4 h. The reaction mixture was diluted withethyl acetate (200 mL), washed with brine, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The resulting oil waschromatographed on silica gel (4×10 cm, elution toluene) to give 2.25 g(70% yield) of the title material as a pale yellow solid. LC (Method A):2.219 min. HRMS(ESI) calcd for C₁₄H₁₃O₃ [M+H]⁺ m/z 229.0859, found229.0859. ¹H NMR (CDCl₃, 600 MHz) δ ppm: 5.12 (s, 2H), 6.43 (d, J=8.25Hz, 1H), 6.52 (d, J=8.46 Hz, 1H), 7.34-7.4 (m, 6H), 10.39 (s, 1H), 11.95(s, 1H).

191C. 1-(4-(Benzyloxy)benzofuran-2-yl)ethanone

A solution of 2-(benzyloxy)-6-hydroxybenzaldehyde (11.10 g, 48.63 mmole)in N,N-dimethylformamide (120 mL) was treated with powdered anhydrouscesium carbonate (15.8 g, 48.63 mmol) added all at once. The resultingmixture was stirred in vacuo for 10 min and then flushed with nitrogen.The reaction flask was placed in a water bath (22° C.) and treated withchloroacetone (4.65 mL, 58.4 mmol) added dropwise over 10 min. Theresulting mixture was then stirred at 22° C. for 18 h (no startingaldehyde left by tlc and formation of the intermediate alkylatedaldehyde). The reaction mixture was then maintained under vacuum (10mbar) for 15 min to remove any un-reacted chloroacetone and then flushedwith nitrogen. Then anhydrous cesium carbonate (1.0 g, 3.1 mmol) wasadded and the mixture was heated at 55° C. and stirred for 40 h (morecesium carbonate, 1 g, was added after 24 h and 32H till completeconversion of the intermediate alkylated aldehyde into the benzofuran asmonitored by TLC. The solid was filtered and washed withN,N-dimethylformamide. The filtrate was evaporated in vacuo and theresidual oil was diluted with ethyl acetate (400 mL), washed with cold0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. Afterdrying over anhydrous magnesium sulfate, evaporation of the solvent gavea thick syrup. Chromatography on silica gel (4.5×12 cm, elutiontoluene-ethyl acetate 2-4%) gave 11.67 g (90% yield) of the titlebenzofuran as a light yellow solid. Recrystallization from a mixture ofethyl acetate (40 mL) and hexane (40 mL) gave colorless prisms (10.50g). LC (Method A): 2.162 min. HRMS(ESI) calcd for C₁₇H₁₅O₃ [M+H]⁺ m/z267.1016, found 267.1022. ¹H NMR (CDCl₃, 600 MHz) δ ppm: 2.56 (s, 3H),5.20 (s, 2H), 6.73 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.3-7.5(m, 6H), 7.63 (s, 1H).

191D. 1-(4-(Benzyloxy)benzofuran-2-yl)-2-bromoethanone

A 250-mL, three-necked flask is equipped with a magnetic stirring barand purged with a nitrogen atmosphere, was charged with anhydroustetrahydrofuran (40 mL) followed by 21.6 mL (21.6 mmol) of a 1M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran. The mixture wascooled to −78° C. and treated with a solution of1-(4-(benzyloxy)benzofuran-2-yl)ethanone (5.00 g, 18.77 mmole intetrahydrofuran (20 mL) added dropwise over 10 min. The resultingmixture was then stirred at −78° C. for 45 min. Thenchlorotrimethylsilane (2.74 mL, 21.6 mmol) was added dropwise over 5 minand the resulting solution was stirred at −78° C. for another 20 min.The cooling bath was then removed and the mixture is allowed to warm toroom temperature over 30 min. The reaction mixture was then quenched byaddition to a cold solution of ethyl acetate (300 mL), saturated sodiumbicarbonate (40 mL) and ice. The organic phase was rapidly dried overanhydrous magnesium sulfate (magnetic stirring) and evaporated in vacuoto give the silyl enol ether as an oil which is co-evaporated withtoluene (20 mL). The silyl enol ether was then dissolved in drytetrahydrofuran (80 mL), cooled to −25° C. and treated with solid sodiumbicarbonate (0.10 g) followed by N-bromosuccinimide (3.34 g, 18.8 mmol)added in small portions over 10 min. The reaction mixture was allowed towarm to 0° C. over 2h and then quenched by addition of ethyl acetate(350 mL) and saturated sodium bicarbonate. The organic phase was washedwith brine, dried over anhydrous magnesium sulfate and evaporated togive an orange oil. Chromatography on silica gel (4.5×12 cm, elutiontoluene-ethyl acetate 0-1%) gave 6.13 g of the title bromomethylketoneas a yellow solid. Recrystallization from ethyl acetate (20 mL) andhexane (40 mL) gave pale yellow prisms (4.93 g, 76% yield). LC (MethodA): 2.215 min. HRMS(ESI) calcd for C₁₇H₁₄BrO [M+H]⁺ m/z 345.0121, found345.0109. ¹H NMR (CDCl₃, 600 MHz) δ ppm: 4.39 (s, 2H), 5.20 (s, 2H),6.75 (d, J=7.86 Hz, 1H), 7.17 (d, J=8.25 Hz, 1H), 7.34-7.46 (m, 6H),7.78 (s, 1H).

191E.6-(4-(Benzyloxy)benzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole

A mixture of 1-(4-(benzyloxy)benzofuran-2-yl)-2-bromoethanone (3.00 g,8.69 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (1.80 g, 10.0 mmol) inisopropanol (100 mL) was heated is a pressure flask equipped with amagnetic stirring bar at 80° C. for 20 h (homogeneous after 20 min andthen formation of a precipitate after 2H. The cooled mixture is thentransferred into five 20 mL microwave vials and then heated in amicrowave apparatus to 150° C. for 30 min. Each vial was then dilutedwith dichloromethane (250 mL) washed with saturated sodium bicarbonate(25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate. Thefractions were combined and concentrated in vacuo. Chromatography of theorange-brown residual solid on silica gel (4×10 cm, slow elution withdichloromethane) gave 2.82 g of the title imidazothiadiazolecontaminated with some 1-(4-(benzyloxy)benzofuran-2-yl)ethanone. Thesolid material was triturated with ethyl acetate (15 mL), filtered,washed with ethyl acetate (10 ml) and dried in vacuo to give 2.37 g (64%yield) of pure title imidazothiadiazole as an off white solid which isused as such for the next step. LC (Method A): 2.425 min. HRMS(ESI)calcd for C₁₉H₁₃BrN₃O₂S [M+H]⁺ m/z 425.9906. found 425.9893. ¹H NMR(CDCl₃, 600 MHz) δ ppm: 5.21 (s, 2H), 6.72 (d, J=8.07 Hz, 1H), 7.13 (d,J=8.26 Hz, 1H), 7.18 (broad t, 1H), 7.25 (s, 1H), 7.32 (broad t, 1H),7.38 (broad t, 2H), 7.47 (broad d, 2H), 8.09 (s, 1H).

191F.6-(4-(Benzyloxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A solution of6-(4-(benzyloxy)benzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole(3.22 g, 7.55 mmol) in a mixture of dichloromethane (400 mL) andmethanol (50 mL) was treated at 22° C. with 6.3 mL of a 25 wt. %solution of sodium methoxide in methanol (30.2 mmol) added in oneportion. More methanol (45 mL) was added and the mixture was stirred for40 min. The reaction mixture was quenched by the addition of 40 mL of 1N hydrochloric acid followed by 10 ml of saturated sodium bicarbonate.The solvent was evaporated under reduced pressure and the residue wasdiluted with dichloromethane (400 mL), washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. Crystallization ofthe white solid residue from 1,2-dichloroethane (30 mL) gave 2.19 g ofthe title material as a white solid. Chromatography of the motherliquors on silica gel (3×10 cm, elution with 0-1% ethylacetate-dichloromethane) gave another 0.46 g of product (total yield,2.65 g, 93%). LC (Method A): 2.379 min. HRMS(ESI) calcd for C₂₀H₁₆N₃O₃S[M+H]⁺ m/z 378.0907, found 378.0911. ¹H NMR (CDCl₃, 600 MHz) δ ppm: 4.18(s, 3H), 5.21 (s, 2H), 6.71 (dd, J=7.4 Hz and J=0.95 Hz, 1H), 7.12-7.17(m, 3H), 7.32 (broad t, 1H), 7.38 (broad t, 2H), 7.47 (broad d, 2H),7.88 (s, 1H).

191G. 2-(2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol

A mixture of6-(4-(benzyloxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(2.640 g, 6.99 mmol) and pentamethylbenzene (7.25 g, 48.9 mmol) indichloromethane (400 mL) was cooled to −78° C. under a nitrogenatmosphere and then treated immediately with 18.2 mL (8.2 mmol) of a 1 Msolution of boron trichloride in dichloromethane added dropwise over 3min. The resulting mixture was stirred at −78° C. for 1 h. The reactionmixture was then quenched by the addition of a solution of sodiumbicarbonate (10.6 g) in water (50 mL) added in one portion. The coolingbath was removed and the resulting mixture was stirred at roomtemperature for 1 h. The solid formed was filtered, washed successivelywith water (50 mL) and dichloromethane (25 mL). The filter cake wasallowed to soak with anhydrous ethanol (10 ml) and then sucked dry. Thewhite solid obtained was then dried under vacuum for a few days overphosphorous pentoxide until constant weight to give 1.459 g (72% yield)of title material. The combined filtrate and washings (organic andaqueous phases from the deprotection step) were diluted withdichloromethane (500 mL) and stirred in a warm water bath till theorganic phase was clear with no apparent solid in suspension. Theorganic phase was collected, dried over anhydrous magnesium sulfate andrapidly filtered while still warm. The filtrate was evaporated and theresidue (product and pentamethylbenzene) was triturated with toluene (20mL). The solid was collected by filtration and washed with toluene (20mL) to give, after drying in vacuo, 0.239 g (12% yield; 84% combinedyield) of title material as a tan solid. LC (Method A): 1.908 min.HRMS(ESI) calcd for C₁₃H₁₀N₃O₃S [M+H]⁺ m/z 288.0437, found 288.0446. ¹HNMR (DMSO-d₆, 600 MHz) δ ppm: 4.46 (s, 3H), 6.58 (d, J=7.8 Hz, 1H), 6.97(d, J=8.15 Hz, 1H), 7.0-7.07 (m, 3H), 8.40 (s, 1H).

Example 1912-Methoxy-6-(4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A mixture of2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (0.100g, 0.349 mmol), triphenylphosphine (0.165 g, 0.627 mmol) and(2-phenylthiazol-4-yl)methanol (Example 3B, 0.080 g, 0.418 mmol) in a 50ml flask was maintained under vacuum for 10 min and then purged withnitrogen. Dry tetrahydrofuran (10 mL) was added and the resultingmixture was slightly warmed and maintained in an ultrasonic bath for 5min. The cooled mixture (still heterogeneous) was treated at 22° C. witha solution of diisopropyl azodicarboxylate (0.113 g, 0.558 mmol) intetrahydrofuran (2 mL) added dropwise over 1 h. The mixture was thenstirred at 2° C. for 4 h. The clear reaction mixture was quenched by theaddition of dichloromethane (100 mL) and saturated sodium bicarbonate(10 mL). The organic phase was washed with brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. Chromatography of theresidue on silica gel (2.5×12 cm, elution 0-3% ethylacetate-dichloromethane) followed by crystallization of the desiredfraction from ethyl acetate (8 mL) gave 0.028 g (24% yield) of the titlematerial as a white solid. LC (Method A): 2.426 min. HRMS(ESI) calcd forC₂₃H₁₇N₄O₃S₂ [M+H]⁺ m/z 461.0737, found 461.0926. ¹H NMR (CDCl₃, 400MHz) δ ppm: 4.22 (s, 3H), 5.45 (d, J=0.78 Hz, 2H), 6.80 (dd, J=7.04,1.57 Hz, 1H), 7.15-7.21 (m, 2H), 7.22 (s, 1H), 7.38 (s, 1H), 7.42-7.51(m, 3H), 7.92 (s, 1H), 7.95-8.03 (m, 2H).

Example 192(S)-2-(1-Fluoroethyl)-6-(6-methoxy-4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

192A. (S)-5-(1-Fluoroethyl)-1,3,4-thiadiazol-2-amine

A 350 mL sealable pressure vessel was charged with thiosemicarbazide(11.17 g, 122.5 mmol) and dry dioxane (100 mL), and the mixture wascooled at 0° C. under an N₂ atmosphere. To this rapidly stirring mixturewas slowly added a solution of (S)-2-fluoropropanoic acid (9.40 g, 102.1mmol, from Fritz-Langhals, E., Tetrahedron Asymmetry, 981 (1994)) indioxane (10 mL). To the resulting mixture was added POCl₃ (11.22 mL,122.5 mmol) dropwise, then the cooling bath was removed and the thickwhite slurry was stirred at room temperature for 1 h. The vessel wasthen sealed and the mixture was heated at 90-95° C. (oil bathtemperature) for 5 h. The cooled mixture was stirred at room temperaturefor 14 h and then the supernatant (two-phase mixture) was decanted andconcentrated under reduced pressure. The lower phase was slowly pouredinto ice water (250 mL) and then the concentrate was also added. Thismixture was rapidly stirred until it was essentially a homogeneous(turbid) solution, and then it was basified to pH 9-9.5 using 40%aqueous NaOH. The resulting slurry was filtered and the filter-cake waswashed with water (Note: LC of this beige solid showed that it containedonly a trace of the desired product, so it was not furtherinvestigated). The combined filtrate was then extracted with EtOAc (×3)and the organic phase was dried (Na₂SO₄) and evaporated to give a creamsolid (10.58 g, 70%) which was the essentially pure product according toLC and LCMS. This material was used as such without furtherpurification. An analytical sample was purified by flash chromatography[Isco/0-20% (MeOH—NH₄OH, 9:1)-DCM] to give a white solid. LC (Method B):0.608 min. MS (ESI) calcd. for C₄H₆FN₃S m/z: 147.03; found: 148.05[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 7.38 (s, 2H), 5.82 (dq, J=6.4, 48.0Hz, 1H), 1.65 (dd, J=6.4, 24.0 Hz, 3H). Chiral LC: S:R=95:5.

192B.(S)-6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole

In a 20 mL vial,1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example 1E,1.501 g, 4.000 mmol) and (S)-5-(1-fluoroethyl)-1,3,4-thiadiazol-2-amine(0.589 g, 4.000 mmol) were suspended in 2-propanol (20 mL) and heated at80° C. for 16 h. The mixture was then heated in a microwave reactor at150° C. for 30 min. The cooled mixture was evaporated to dryness and theobtained residue was taken up in CH₂Cl₂ (200 mL), washed (saturatedaqueous NaHCO₃), dried (Na₂SO₄) and concentrated. The residue waspurified on the ISCO (0-30% acetone-hexanes) to give the title compound(0.922 g, 54.4%) as a pale yellow solid. LC (Method B): 2.403 min. MS(ESI) calcd. for C₂₂H₁₉FN₃O₃S [M+H]⁺ m/z: 424.1131; found: 424.1146. ¹HNMR (400 MHz, DMSO-d₆) d ppm 8.61 (s, 1H) 7.51 (d, J=7.4 Hz, 2H) 7.42(t, J=7.6 Hz, 2H) 7.35 (t, J=7.0 Hz, 1H) 7.08 (s, 1H) 6.83-6.85 (m, 1H)6.54 (d, J=1.2 Hz, 1H) 6.16 (dq, J=47.1, 6.4 Hz, 1H) 5.26 (s, 2H) 3.80(s, 3H) 1.79 (dd, J=24.5, 6.8 Hz, 3H).

192C.(S)-2-(2-(1-Fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol

A mixture of(S)-6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole(0.152 g, 0.359 mmol) and pentamethylbenzene (0.374 g, 2.52 mmol) indichloromethane (24 ml, 373 mmol) was cooled to −78° C. under nitrogenatmosphere and then treated immediately with boron trichloride 1.0M indichloromethane (1 ml, 1.000 mmol) added dropwise over 3 min. Theresulting mixture was stirred at −78° C. for 1 h. The reaction mixturewas quenched by addition of a solution of sodium bicarbonate (0.71 g) inwater (12 mL) added in one portion. The cooling bath was removed and theresulting mixture was stirred at room temperature for 1 h. The solidformed was filtered, washed successively with water (8 mL) anddichloromethane (8 mL). The filter cake was soaked with anh. ethanol andsuck dried. The white solid obtained was dried under vacuum on P₂O₅ for36 h. LC (Method B): 2.038 min. MS (ESI) calcd. for C₁₅H₁₃FN₃O₃S [M+H]⁺m/z: 334.0656; found: 334.0680. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.06(s, 1H) 8.56 (s, 1H) 7.09 (s, 1H) 6.67 (s, 1H) 6.26-6.28 (m, 1H) 6.16(dq, J=46.9, 6.4 Hz, 1H) 3.76 (s, 3H) 1.80 (dd, J=24.7, 6.3 Hz, 3H).

Example 192(S)-2-(1-Fluoroethyl)-6-(6-methoxy-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a mixture of(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(0.050 g, 0.150 mmol), (2-phenylthiazol-4-yl)methanol (Example 3B, 0.086g, 0.450 mmol) and triphenylphosphine (0.118 g, 0.450 mmol) under N₂ wasadded dry THF (3 mL). To the resulting light amber solution was added asolution of DIAD (0.087 mL, 0.450 mmol) in dry THF (2 mL) dropwise over2 h to give light yellow-brown solution. After stirring at roomtemperature for an additional 30 min, LC showed that no startingmaterial remained. The volatiles were then removed under reducedpressure to give an amber gum. Flash chromatography (Isco/0-20%ether-DCM) afforded the product as a nearly colorless gum. This gum wastriturated with a minimum volume of MeOH and the resulting slurry wasfiltered and the filter-cake was washed with a minimum volume of MeOHand then dried in vacuo to give the title material (0.048 g, 63.2%) as asolid which was further lyophilized from MeCN—H₂O to give a cream solid.LC (Method A): 2.453 min. HRMS(ESI) calcd for C₂₅H₂₀FN₄O₃S₂ [M+H]⁺ m/z507.096, found 506.098. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.67 (s, 1H),8.05-8.02 (m, 2H), 7.96 (s, 1H), 7.60-7.56 (m, 3H), 7.20 (d, J=0.8 Hz,1H), 6.93 (dd, J=0.8, 2.0 Hz, 1H), 6.73 (d, J=1.6 Hz, 1H), 6.23 (dq,J=6.7, 47.0 Hz, 1H), 5.45 (s, 2H), 3.89 (s, 3H), 1.86 (d, J=6.7, 24.6Hz, 3H).

Example 193(S)-4-(4-(((2-(2-(1-Fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)morpholine

A solution of(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 192C, 0.050 g, 0.150 mmol) in DMF (2 mL) was stirred under N₂and then 4-(4-(bromomethyl)thiazol-2-yl)morpholine (0.047 g, 0.180 mmol)was added, followed by powdered potassium carbonate (0.062 g, 0.450mmol), and the mixture was stirred at room temperature for 4 h. Themixture was then diluted with saturated aqueous NH₄Cl and extracted withDCM (×2). The organic extract was washed (brine), dried (Na₂SO₄) andevaporated to give a light amber gum. Flash chromatography (Isco/0-100%EtOAc-hexane) afforded(S)-4-(4-(((2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)morpholine(0.055 g, 71.1%) as a colorless gum, which was lyophilized fromMeCN-water as a cream solid. LC (Method A): 2.271 min. HRMS(ESI): calcdfor C₂₃H₂₃FN₅O₄S₂ [M+H]⁺ m/z 516.118; found 516.121. ¹H NMR (400 MHz,DMSO-d₆): δ 8.54 (s, 1H), 7.02 (s, 1H), 6.92 (s, 1H), 6.77 (s, 1H), 6.52(d, J=1.96 Hz, 1H), 6.10 (dq, J=6.26, 46.95 Hz, 1H), 5.01 (s, 2H), 3.74(s, 3H), 3.64 (t, J=4.89 Hz, 4H), 3.31 (t, J=4.89 Hz, 4H), 1.73 (dd,J=6.26, 24.65 Hz, 3H).

Example 194(S)-4-(4-(((2-(2-(1-Fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

To a flame-dried flask was added(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 192C, 0.050 g, 0.150 mmol) and4-(4-(hydroxymethyl)thiazol-2-yl)-N,N-dimethylbenzamide (Example 36B,0.047 g, 0.180 mmol), then the flask was flushed with N₂ and dry THF (3mL) was added. To the resulting suspension was addedtri-n-butylphosphine (0.097 mL, 0.375 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (0.096 g, 0.375 mmol) in dry THF (2 mL)was added dropwise (via a syringe pump) over 30 min. The resultingmixture was stirred at room temperature for another 15 min and then themixture was diluted with EtOAc, washed (saturated aqueous NaHCO₃, H₂O,brine), dried (Na₂SO₄) and evaporated to give a yellow semi-solid. Flashchromatography (Isco/0-100% EtOAc-DCM) afforded a colorless gum whichwas triturated with MeCN. The resulting slurry was filtered and thefilter-cake washed with MeCN and then dried in vacuo to give a paleyellow solid which was lyophilized from MeCN-water to give(S)-4-(4-(((2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide(0.066 g, 76%) as a pale yellow solid. LC (Method A): 2.345 min.HRMS(ESI): calcd for C₂₈H₂₅FN₅O₄S₂ [M+H]⁺ m/z 578.133; found 578.133. ¹HNMR (400 MHz, DMSO-d₆): δ 8.54 (s, 1H), 7.96 (d, J=8.61 Hz, 2H), 7.89(s, 1H), 7.48 (d, J=8.61 Hz, 2H), 7.07 (s, 1H), 6.80 (s, 1H), 6.60 (d,J=1.96 Hz, 1H), 6.10 (dq, J=6.65, 46.95 Hz, 1H), 5.33 (s, 2H), 3.76 (s,3H), 2.94 (br s, 3H), 2.87 (br s, 3H), 1.73 (dd, J=6.65, 24.65 Hz, 3H).

Example 195(S)-6-(6-Fluoro-4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)-2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole

A solution of2-bromo-1-(6-fluoro-4-(((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone(Example 179E, 0.020 g, 0.045 mmol) and(S)-5-(1-fluoroethyl)-1,3,4-thiadiazol-2-amine (Example 192A, 0.008 g,0.052 mmol) in propan-2-ol (2 mL) was heated at 70° C. for 16 h. Thecooled reaction mixture was then partitioned between dichloromethane andsaturated aqueous sodium bicarbonate. The organic phase was separated,washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residue obtained was chromatographed onsilica gel (ISCO, elution gradient of ethyl acetate in dichloromethane)to give the title compound (0.015 g, 68%) as a white solid. LC (MethodA): 2.493 min. HRMS(ESI) calcd for C₂₄H₁₆F₂N₄O₂S₂ [M+H]⁺ m/z: 494.0761;found 495.0776. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.07 (s, 1H), 7.93-8.02(m, 2H), 7.42-7.51 (m, 3H), 7.38 (s, 1H), 7.25 (s, 1H), 6.87-6.94 (m,1H), 6.64 (dd, J=11.35, 1.96 Hz, 1H), 5.65-6.04 (m, 1H), 5.41 (s, 2H),1.80-1.95 (m, 3H).

Example 196(S)-4-(4-(((2-(2-(1-Fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol

To a flame-dried flask was added(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 192C, 0.040 g, 0.120 mmol) and4-(4-(hydroxymethyl)thiazol-2-yl)tetrahydro-2H-pyran-4-ol (Example 118B,0.032 g, 0.150 mmol), then the flask was flushed with N₂ and dry THF (2mL) was added. To the resulting suspension was addedtri-n-butylphosphine (0.078 mL, 0.300 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (0.076 g, 0.300 mmol) in dry THF (2 mL)was added dropwise (via syringe pump) over 30 min. The resulting mixturewas stirred at room temperature for 2 h, at which time moretri-n-butylphosphine (0.078 mL, 0.300 mmol) and1,1′-(azodicarbonyl)dipiperidine (0.076 g, 0.300 mmol) were added andstirring was continued for 16 h. The mixture was then diluted withEtOAc, washed (saturated aqueous NaHCO₃, H₂O, brine), dried (Na₂SO₄) andevaporated to give a golden-yellow gum. Flash chromatography(Isco/0-100% EtOAc-DCM) afforded the title compound (0.047 g, 73.8%) asa colorless gum which was lyophilized from MeCN-water as an off-whitesolid. LC (Method A): 2.236 min. HRMS(ESI): calcd for C₂₄H₂₄FN₄O₅S₂[M+H]⁺ m/z 531.117; found 531.120. ¹H NMR (400 MHz, DMSO-d₆): δ 8.54 (s,1H), 7.64 (s, 1H), 7.02 (s, 1H), 6.78 (s, 1H), 6.57 (d, J=1.96 Hz, 1H),6.11 (dq, J=6.65, 46.95 Hz, 1H), 6.08 (s, 1H), 5.21 (s, 2H), 3.75 (s,3H), 3.67 (m, 4H), 2.05 (ddd, J=5.48, 11.35, 13.69 Hz, 2H), 1.73 (dd,J=6.65, 25.04 Hz, 3H), 1.61 (br d, J=12.91 Hz, 3H).

Example 197

(S)-2-(1-Fluoroethyl)-6-(4-((2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a solution of4-(bromomethyl)-2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazole (Example119C, 0.016 g, 0.057 mmol) in DMF (1.5 mL) was added(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 192C, 0.017 g, 0.052 mmol), followed by freshly powderedpotassium carbonate (0.022 g, 0.156 mmol). The mixture was stirred in asealed vial at room temperature for 2 h and then it was diluted withsaturated aqueous NH₄Cl and the resulting mixture was filtered and thefilter-cake was washed with water. The wet, gummy residue was taken upin DCM and the solution was washed (saturated aqueous NaHCO₃), dried(Na₂SO₄) and evaporated to give a yellow gum. Flash chromatography(Isco/0-40% EtOAc-DCM) afforded the slightly impure product as a paleyellow gum. This material was repurified by preparative HPLC (Method A)to give pure(S)-2-(1-fluoroethyl)-6-(4-((2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(0.020 g, 72.3%) as a solid. LC (Method A): 2.400 min. HRMS(ESI): calcdfor C₂₄H₂₃F₂N₄O₄S₂ [M+H]⁺ m/z 533.113; found 533.115. ¹H NMR (400 MHz,DMSO-d₆): δ 8.57 (s, 1H), 7.91 (s, 1H), 7.07 (s, 1H), 6.83 (m, 1H), 6.61(d, J=1.57 Hz, 1H), 6.13 (dq, J=6.65, 46.56 Hz, 1H), 5.30 (s, 2H), 3.81(m, 2H), 3.79 (s, 3H), 3.67 (dt, J=1.57, 10.96 Hz, 2H), 2.33-2.16 (m,2H), 2.05 (m, 2H), 1.73 (dd, J=6.65, 24.65 Hz, 3H).

Example 1984-(4-(((2-(2-((S)-1-Fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol

To a flame-dried flask was added(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 192C, 0.630 g, 1.890 mmol) and4-(4-(hydroxymethyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(Example 121B, 0.552 g, 2.268 mmol), then the flask was flushed with N₂and dry THF (20 mL) was added. To the resulting suspension was addedtri-n-butylphosphine (1.227 mL, 4.72 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (1.204 g, 4.72 mmol) in dry THF (10 mL)was added dropwise (via syringe pump) over 30 min. The resulting mixturewas stirred at room temperature for another 2 h and then it was dilutedwith EtOAc, washed (saturated aqueous NaHCO₃, H₂O, brine), dried(Na₂SO₄) and evaporated to give a yellow semi-solid. Flashchromatography (Isco/0-100% EtOAc-DCM) afforded the product as a solid.This solid was triturated with MeCN and the resulting slurry wasfiltered and the filter-cake washed with MeCN and then dried in vacuo togive4-(4-(((2-(2-((S)-1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)-methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(0.823 g, 78%) as an off-white solid. LC (Method A): 2.324 min.HRMS(ESI): calcd for C₂₆H₂₈FN₄O₅S₂ [M+H]⁺ m/z 559.149; found 559.151. ¹HNMR (400 MHz, DMSO-d₆): δ 8.54 (s, 1H), 7.70 (s, 1H), 7.01 (s, 1H), 6.79(s, 1H), 6.62 (d, J=1.57 Hz, 1H), 6.11 (dq, J=6.65, 46.95 Hz, 1H), 6.03(s, 1H), 5.25 (s, 2H), 3.77 (m, 2H), 3.76 (s, 3H), 2.01 (d, J=12.91 Hz,2H), 1.74 (dd, J=6.65, 25.04 Hz, 3H), 1.39 (t, J=12.91 Hz, 2H), 1.01 (d,J=6.26 Hz, 6H).

Example 1996-(4-((2-(4-Fluoro-2,6-dimethyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-((S)-1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole

To an ice-cold suspension of4-(4-(((2-(2-((S)-1-fluoroethyl)imidazo[2,1-b][1,3,4]thia-diazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol(Example 198, 0.021 g, 0.038 mmol) in DCM (3 mL) under N₂ was added DAST(0.012 mL, 0.094 mmol) dropwise and the resulting mixture was stirred at0° C. for 20 min. Another aliquot of DAST (0.007 mL, 0.053 mmol) wasadded, the cooling bath was removed and the resulting pale yellowsolution was stirred at room temperature for 16 h. The reaction mixturewas then re-cooled at 0° C. and quenched by the dropwise addition ofsaturated aqueous NaHCO₃ (3 mL). The mixture was vigorously stirred at0° C. for 5 min and then the cooling bath was removed and stirring wascontinued until no more gas evolution was observed. The organic phasewas subsequently separated and applied directly to a silica gelpre-column. Flash chromatography (Isco/0-100% EtOAc-hexane) afforded6-(4-((2-(4-fluoro-2,6-dimethyltetrahydro-2H-pyran-4-yl)thiazol-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-((S)-1-fluoroethyl)imidazo-[2,1-b][1,3,4]thiadiazole(0.014 g, 66.4%) as a colorless gum which was lyophilized fromMeCN-water to give a white solid. NMR indicated that this was a 3:2mixture of isomers. LC (Method A): 2.487 min. HRMS(ESI): calcd forC₂₆H₂₇F₂N₄O₄S₂ [M+H]⁺ m/z 561.144; found 561.146. ¹H NMR (400 MHz,DMSO-d₆): δ 8.54 (s, 0.4H), 8.53 (s, 0.6H), 7.94 (s, 0.6H), 7.85 (s,0.4H), 7.03 (s, 0.4H), 7.02 (s, 0.6H), 6.79 (m, 1H), 6.59 (d, J=1.57 Hz,0.6H), 6.57 (d, J=1.96 Hz, 0.4H), 6.10 (dq, J=6.65, 46.56 Hz, 1H), 5.30(s, 1.2H), 5.25 (s, 0.8H), 3.76 (m, 0.8H), 3.75 (s, 1.2H), 3.74 (s,1.8H), 3.53 (m, 1.2H), 2.38 (m, 1H), 2.08 (m, 1H), 1.83-1.61 (m, 2H),1.73 (dd, J=6.65, 25.04 Hz, 3H), 1.10 (d, J=6.26 Hz, 2.4H), 1.01 (d,J=6.26 Hz, 3.6H).

Example 200(S)-4-(4-(((2-(2-(1-Fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol

To a flame-dried flask was added(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 192C, 0.050 g, 0.150 mmol) and4-(4-(hydroxymethyl)-5-methylthiazol-2-yl)tetrahydro-2H-pyran-4-ol(Example 124D, 0.038 g, 0.165 mmol), then the flask was flushed with N₂and dry THF (3 mL) was added. To the resulting suspension was addedtri-n-butylphosphine (0.097 mL, 0.375 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (0.096 g, 0.375 mmol) in dry THF (2 mL)was added dropwise (via syringe pump) over 30 min. The resulting mixturewas stirred at room temperature for another 15 min and then the mixturewas diluted with EtOAc, washed (saturated aqueous NaHCO₃, H₂O, brine),dried (Na₂SO₄) and evaporated to give a pale yellow waxy solid. Flashchromatography (Isco/0-100% EtOAc-DCM) afforded the title compound(0.061 g, 74.7%) as a colorless gum which was lyophilized fromMeCN-water as a solid. LC (Method A): 2.256 min. HRMS(ESI): calcd forC₂₅H₂₆FN₄O₅S₂ [M+H]⁺ m/z 545.133; found 545.132. ¹H NMR (400 MHz,DMSO-d₆): δ 8.54 (s, 1H), 6.94 (s, 1H), 6.78 (m, 1H), 6.61 (d, J=1.96Hz, 1H), 6.09 (dq, J=6.65, 46.95 Hz, 1H), 5.99 (br s, 1H), 5.14 (s, 2H),3.75 (s, 3H), 3.65 (m, 4H), 2.40 (s, 3H), 2.02 (m, 2H), 1.72 (dd,J=6.65, 24.65 Hz, 3H), 1.58 (d, J=11.74 Hz, 3H).

Example 2016-Methoxy-2-(2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-4-(((2-phenylthiazol-4-yl)methoxy)benzo[d]oxazole

201A. Ethyl 2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate

A mixture of 2-amino-5-methylthio-1,3,4-thiadiazole (25.0 g, 0.17 mol),ethyl 3-bromopyruvate (23.7 mL, 0.189 mol) and ethanol (125 mL) in a 350mL sealable vessel was heated at 150° C. (oil bath temperature) for 20min. The cooled mixture was then concentrated to dryness and the residuewas partitioned with ethyl acetate-saturated aqueous NaHCO₃. The organicphase was separated, washed (brine), dried (MgSO₄), filtered andconcentrated to dryness. The obtained residue was taken up in a minimumvolume of dichloromethane and the resulting slurry was filtered and thefilter-cake was washed with a little dichloromethane. The solid residuewas dried in vacuo to give recoveredamino-5-methylthio-1,3,4-thiadiazole (3.7 g, 15%). The obtained filtratewas subsequently evaporated and the residue was crystallized from aminimum volume of hot ethanol to give the title compound as a beigecrystalline solid (10.8 g, 26%). LC (Method B): 1.267 min. ¹H NMR (600MHz, DMSO-d₆) δ ppm: 8.76 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 2.78 (s, 3H),1.28 (t, J=7.2 Hz, 3H).

201B. 2-(Methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylic acid

In a sealable microwave vial, a solution of ethyl2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (1.22 g,5.0 mmol) in glacial acetic acid (15 mL) was treated with 48% HBr (1.42mL, 12.5 mmol) dropwise. The vial was then sealed and the resultingslurry was heated at 150° C. (microwave) for 1.5 h. The cooled mixturewas then filtered and the filter-cake was washed with a minimum volumeof glacial acetic acid and then DCM. After drying in vacuo, thisafforded the essentially pure HBr salt of title compound (1.37 g, 92%)as a white solid. This material was used as such in the next step. LC(Method A): 1.313 min. LCMS (APCI): calcd. for C₆H₆N₃O₂S₂ [M+H]⁺ m/z215.99, found 216.00. ¹H NMR (600 MHz, DMSO-d₆) δ ppm: 8.63 (s, 1H),2.75 (s, 3H).

201C. 2-(Methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carbonyl chloride

To a stirred suspension of2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylic acid (15.0g, 0.070 mol) in DCM (350 mL) was added oxalyl chloride (29.5 mL, 0.348mol) followed by DMF (1 drop). Gas evolution was observed and thereaction mixture was stirred at room temperature for 3.5 h. Thesuspension was then concentrated to dryness to give the title compoundas a light-yellow solid (quantitative yield assumed) which was used assuch in the next step. LC (Method A): 1.686 min; ¹H NMR (600 MHz,DMSO-d₆) δ ppm 8.68 (s, 1H) 2.78 (s, 3H).

201D.N-(2,6-Dihydroxy-4-methoxyphenyl)-2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxamide

To an ice-cold suspension of2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carbonyl chloride(0.378 g, 1.62 mmol) and 2-amino-5-methoxybenzene-1,3-diol (0.251 g,1.62 mmol) in DMF (10 mL) was added triethylamine (1.13 mL, 8.10 mmol).The reaction mixture was stirred for 5 min and then the cooling bath wasremoved and stirring was continued at room temperature for 16 h. Theresulting mixture was evaporated to dryness and the residue waspartitioned with DCM-brine-water (2:1:1). The organic phase wasseparated, dried (MgSO₄) and evaporated to dryness. The residue wastriturated with MeOH and the product was filtered off and dried in vacuoto give the title compound as a beige solid (0.100 g, 0.284 mmol,17.5%). LC (Method E): 1.828 min. HRMS(ESI): calcd for C₁₃H₁₃N₄O₄S₂[M+H]⁺ m/z 353.0378, found 353.0603. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:10.26 (m, 2H), 9.26 (d, J=9.4 Hz, 1H), 8.76 (s, 1H), 6.01 (d, J=2.3 Hz,2H), 3.66 (s, 3H), 2.81 (s, 3H).

201E.6-Methoxy-2-(2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazol-4-ol

A microwaveable vessel was charged withN-(2,6-dihydroxy-4-methoxyphenyl)-2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxamide(0.086 g, 0.244 mmol), TFA (1 mL) and acetic acid (1 mL). The vessel wasthen sealed and heated in a microwave at 200° C. for 10 min. Thereaction mixture was allowed to stand at room temperature for 16 h andthe resulting brown crystalline solid was filtered off and dried invacuo to give the title compound (0.044 g, 0.098 mmol, 40%). LC (MethodE): 1.961 min. HRMS(ESI): calcd for C₁₃H₁₁N₄O₃S₂ [M+H]⁺ m/z 335.0273,found 335.0505. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.85 (s, 1H), 6.79 (d,J=1.8 Hz, 1H), 6.36 (d, J=1.8 Hz, 1H), 3.77 (s, 3H), 2.81 (s, 3H).

Example 2016-Methoxy-2-(2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-4-((2-phenylthiazol-4-yl)methoxy)benzo[d]oxazole

A suspension of6-methoxy-2-(2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazol-4-ol(0.080 g, 0.239 mmol) and 2-(bromomethyl)-4-phenylthiazole (0.122 g,0.479 mmol) in N,N-dimethylformamide (3 mL) was maintained under vacuum(10 mbar) for 5 min, then the flask was flushed with nitrogen andfreshly powdered anhydrous potassium carbonate (0.105 g, 0.756 mmol) wasadded all at once. The resulting mixture was stirred at room temperaturefor 16 h, then the reaction was quenched with 1N HCl (2 mL) and finallyit was partitioned between dichloromethane (150 mL) and saturatedaqueous sodium bicarbonate (20 mL). The organic phase was separated,washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residue was triturated with acetonitrile andthe desired product was filtered off and dried in vacuo to give6-methoxy-2-(2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-4-((2-phenylthiazol-4-yl)methoxy)benzo[d]oxazole(0.068 g, 0.134 mmol, 56.0%) as a white solid. LC (Method F): 2.653 min.HRMS(ESI): calcd for C₂₃H₁₈N₅O₃S₃ [M+H]⁺ m/z 508.0572, found 508.0607.¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 8.88 (s, 1H), 7.94 (m, 2H), 7.85 (s,1H), 7.51-7.46 (m, 3H), 6.96 (d, J=2.0 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H),5.44 (s, 2H), 3.80 (s, 3H), 2.77 (s, 3H).

Example 2022-(2-(1,1-Difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-4-((2-phenylthiazol-4-yl)methoxy)furo[3,2-c]pyridine

202A. 4-(Benzyloxy)furo[3,2-c]pyridine

A microwave vial was charged with furo[3,2-c]pyridin-4(5H)-one (0.676 g,5.0 mmol, prepared as described in EP 2100895) and benzyl bromide (1.189mL, 10.0 mmol) and then n-hexane (20 mL) and silver carbonate (50% onCELITE®, 3.31 g, 6.00 mmol) were added. The resulting reaction mixturewas then heated at 125° C. in the microwave reactor for 10 min. Thecrude reaction mixture was filtered, the filter-cake was washed withethyl acetate and the filtrate was concentrated under reduced pressure.The crude residue obtained was purified by column chromatography(Isco/25 g cartridge) eluting with a gradient of ethyl acetate inhexanes (from 0 to 5%) to give the title compound (0.766 g, 68%). LC(Method A): 2.127 min. LCMS (APCI): calcd for C₁₄H₁₂NO₂ [M+H]⁺ m/z226.09, found 226.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 5.54 (s, 2H),6.86-6.88 (m, 1H), 7.11-7.13 (m, 1H), 7.30-7.42 (m, 3H), 7.48-7.53 (m,2H), 7.56 (d, J=2.4 Hz, 1H), 8.02 (d, J=6.3 Hz, 1H).

202B. 1-(4-(Benzyloxy)furo[3,2-c]pyridin-2-yl)ethanone

A solution of 4-(benzyloxy)furo[3,2-c]pyridine (1.532 g, 6.80 mmol) indry THF (40 mL) was cooled at −78° C. under nitrogen and n-butyllithium(2.5 M in hexanes, 3.40 mL, 8.50 mmol) was added dropwise. After theaddition was complete the reaction mixture was stirred for 20 min beforeN,N-dimethylacetamide (1.265 mL, 13.60 mmol) was added. The reactionmixture was stirred for 1 h at −78° C. and then it was warmed to −30° C.over 4 h. The reaction mixture was subsequently poured onto crushed iceand the mixture was extracted with ethyl acetate (×2). The combinedorganic extracts were washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product was purified by column chromatography(Isco, 40 g cartridge) eluting with a gradient of ethyl acetate inhexanes (from 0 to 25%) to give the title compound (1.15 g, 63%). LC(Method A): 2.129 min. LCMS (APCI): calcd for C₁₆H₁₄NO₃ [M+H]⁺ m/z268.10, found 268.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 2.59 (s, 3H), 5.56(s, 2H), 7.16 (dd, J=1.2, 6.3 Hz, 1H), 7.33-7.43 (m, 3H), 7.48-7.52 (m,2H), 7.58 (d, J=0.8 Hz, 1H), 8.16 (d, J=6.3 Hz, 1H).

202C. 1-(4-(Benzyloxy)furo[3,2-c]pyridin-2-yl)-2-bromoethanone

To a solution of LiHMDS (1 M in THF, 5.15 mL, 5.15 mmol) in dry THF (35mL), stirred at −78° C. under nitrogen, was added a solution of1-(4-(benzyloxy)furo[3,2-c]pyridin-2-yl)ethanone (1.148 g, 4.30 mmol) inTHF (15 mL) dropwise. After 45 min trimethylchlorosilane (0.604 mL, 4.72mmol) was added and the reaction was stirred at the same temperature foranother 30 min. The cooling bath was then removed and the reaction wasstirred at room temperature for 30 min before being quenched withsaturated aqueous NaHCO₃ (15 mL) and diluted with cold ethyl acetate(100 mL). The isolated organic layer was dried over MgSO₄, filtered andconcentrated. The residue obtained was co-evaporated twice with tolueneto remove all traces of water. The silyl enol ether obtained was thendissolved in dry THF (25 mL) and cooled to −30° C. under nitrogen. Tothe resulting solution was added sodium bicarbonate (0.072 g, 0.859mmol), followed by NBS (0.726 g, 4.08 mmol) (the latter added in smallportions over 15 min). After complete addition, the reaction mixture wasallowed to warm to 0° C. over 2h, while being monitored by LCMS. Uponcompletion of the reaction, the crude reaction mixture was diluted withEtOAc, washed with saturated aqueous sodium bicarbonate and brine, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue obtained was purified by column chromatography (Isco, 40 gcartridge) eluting with hexanes/dichloromethane/ethyl acetate (from100:0:0 to 0:100:0 to 0:50:50) to give the title compound (0.225 g,15%). LC (Method A): 2.209 min. LCMS (APCI): calcd for C₁₆H₁₃BrNO₃[M+H]⁺ m/z 346.01, found 346.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 4.38 (s,2H), 5.56 (s, 2H), 7.17 (dd, J=1.2, 6.3 Hz, 1H), 7.32-7.44 (m, 3H),7.48-7.52 (m, 2H), 7.73 (d, J=0.8 Hz, 1H), 8.19 (s, 1H).

202D. 5-(1,1-Difluoroethyl)-1,3,4-thiadiazol-2-amine

A modification of a reported procedure was used (cf. He, J. et al.,Chinese Chemical Letters, 19:1281 (2008)). Thus, to an ice-coldsuspension of thiosemicarbazide (4.97 g, 54.5 mmol) in dioxane (45 mL)was slowly added a solution of the 2,2-difluoropropanoic acid (4.50 g,40.9 mmol) in dioxane (5 mL). To the resulting thick off-white slurrywas added POCl₃ (4.99 mL, 54.5 mmol) dropwise and then the cooling bathwas removed and the mixture was stirred at room temperature for 1 h. Thevessel was then sealed and the stirred mixture was heated at 90-95° C.(oil bath temperature) for 5 h. The resulting turbid mixture wasconcentrated under reduced pressure and the concentrate was poured intoice water (150 mL). This mixture was basified to ca. pH 9 using 40%aqueous NaOH and the resulting slurry was filtered and the residue waswashed with water, then with ether and finally with hexanes. The residuewas dried in vacuo to give the title compound (4.31 g, 64%) as a whitesolid which was used as such in the next step. LC (Method B): 1.045 min.LCMS (APCI): calcd. for C₄H₆F₂N₃S [M+1]⁺ m/z 165.02; found 166.0. ¹H NMR(600 MHz, DMSO-d₆) δ ppm: 7.69 (s, 2H), 2.06 (t, J=19.0 Hz, 3H).

202E.2-(2-(1,1-Difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)furo[3,2-c]pyridin-4ol

A microwave vial was charged with1-(4-(benzyloxy)furo[3,2-c]pyridin-2-yl)-2-bromoethanone (0.100 g, 0.289mmol), 5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-amine (0.0573 g, 0.347mmol) and i-PrOH (2.5 mL). The resulting suspension was heated at 80° C.under microwave radiation for 1 h and then at 150° C. for another 90min. The crude reaction mixture was diluted with dichloromethane, washedwith saturated aqueous sodium bicarbonate, dried over MgSO₄, filteredand concentrated. The crude residue obtained was adsorbed on a silicagel pre-column and the product was purified by column chromatography(Isco, 12 g cartridge) eluting with a gradient of a (1% NH₄OH-9%MeOH-90% CH₂Cl₂) in dichloromethane (from 0 to 10%) to give the titlecompound (0.054 g, 58%). LC (Method A): 2.015 min. HRMS(ESI): calcd forC₁₃H₉F₂N₄O₂S [M+H]⁺ m/z 323.0414, found 323.0448. ¹H NMR (DMSO-d₆, 400MHz) δ ppm: 2.24 (t, J=19.6 Hz, 3H), 6.70 (d, J=7.4 Hz, 2H), 7.11 (s,1H), 7.34 (dd, J=5.9, 7.0 Hz, 1H), 8.76 (s, 1H), 11.55 (br s, 1H).

Example 2022-(2-(1,1-Difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-4-(((2-phenylthiazol-4-yl)methoxy)furo[3,2-c]pyridine

A microwave vial was charged with2-(2-(1,1-difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)furo[3,2-c]pyridin-4-ol(0.010 g, 0.031 mmol) and 4-(bromomethyl)-2-phenylthiazole (0.0087 g,0.034 mmol) before n-hexane (1 mL) and silver carbonate (50% on CELITE®,0.0107 g, 0.039 mmol) were added. The resulting reaction mixture wasthen heated at 150° C. under microwave radiation for 1 h. The crudereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue obtained was purified by preparative HPLC(Method A) to give the title compound (0.0025 g, 16%). LC (Method A):2.477 min. HRMS(ESI): calcd for C₂₃H₁₆F₂N₅O₂S₂ [M+H]⁺ m/z 496.0714,found 496.0754. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 2.24 (t, J=19.2 Hz,3H), 5.67 (s, 2H), 7.29 (d, J=1.2 Hz, 1H), 7.41 (dd, J=0.8, 5.9 Hz, 1H),7.46-7.55 (m, 3H), 7.84-7.85 (m, 1H), 7.94-7.99 (m, 2H), 8.09 (d, J=5.9Hz, 1H), 8.88 (s, 1H).

Example 2034-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-phenylthiazole

203A.2-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine

A mixture of 6-methylpyridazin-3-amine (1.52 g, 13.93 mmol),1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example 1E,5.00 g, 13.33 mmol) and 2-propanol (110 mL) in a 150 mL pressure flaskwas heated at 65° C. The mixture was almost homogeneous after 30 min ofheating and precipitated again after 40 min. The mixture was heated fora total of 48 h. The cooled reaction mixture was diluted withdichloromethane (600 mL), washed with saturated sodium bicarbonate,brine and dried over anhydrous magnesium sulfate. Evaporation gave anorange brown solid which was chromatographed on silica gel (4×9 cm,elution dichloromethane-ethyl acetate 0-5%) to give the title material(3.64 g) as an orange brown solid. The solid was boiled with ethylacetate (30 mL, partially soluble) and allowed to stand at roomtemperature for 2 h. The crystals were collected by filtration and driedovernight in vacuo to give the title material (3.440 g, 67%) as paleyellow brown needles. LC (Method A): 2.279 min. HRMS(ESI) calcd forC₂₃H₂₀N₃O₃ [M+H]⁺ m/z 386.1505, found 386.1532. ¹H NMR (CDCl₃, 400 MHz)δ ppm: 2.59 (s, 3 H), 3.86 (s, 3 H), 5.21 (s, 2 H), 6.43 (d, J=1.96 Hz,1 H), 6.75 (broad d, 1 H), 6.94 (d, J=9.39 Hz, 1 H), 7.31-7.38 (m, 2 H),7.38-7.45 (m, 2 H), 7.50 (broad d, J=7.43 Hz, 2 H), 7.82 (d, J=9.39 Hz,1 H), 8.19 (s, 1 H).

203B. 6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol

A solution of2-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine(Example 39A, 1.00 g, 2.59 mmol) in a mixture of dichloromethane (420mL) and methanol (150 mL) in a 1 L flask was hydrogenated over 10%Palladium over carbon (0.30 g, i.e., 30 mg Pd) and under 1 atm ofhydrogen for 6 h. The reaction mixture was maintained under vacuum for 2min and then flushed with nitrogen. The catalyst was filtered and washedwith warm dichloromethane-methanol (8:2, 100 mL) and the combinedfiltrate was concentrated under reduced pressure. The yellow residue wasboiled with 1,2-dichloroethane (30 mL) and allowed to stand at roomtemperature for 18 h. The solid was filtered (contains methanol by NMR)and dried in vacuo at 120° C. for 12 h to give the title material (0.760g, 99% yield) of a yellow solid. LC (Method A): 1.844 min. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm: 2.54 (s, 3H), 3.77 (s, 3H), 6.28 (d, J=1.96Hz, 1H), 6.70 (dd, J=1.96, 1.17 Hz, 1H), 7.20 (d, J=9.39 Hz, 1H), 7.24(d, J=0.78 Hz, 1H), 8.03 (d, J=9.78 Hz, 1H), 8.50 (s, 1H), 10.10 (br s,1H).

Example 2034-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-phenylthiazole

In a 100 mL round-bottom flask, a suspension of6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol (0.190g, 0.643 mmol) and 4-(bromomethyl)-2-phenylthiazole (0.180 g, 0.708mmol) in DMF (5 mL) was purged under vacuum and N₂ for 10 min. Thereaction was treated with potassium carbonate (0.24 g, 1.737 mmol) andstirred at 22° C. for 18 hours, then diluted with DCM and washed withwater (1×), brine (1×). The organic layers were dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was purifiedby silica gel chromatography (2.5×10 cm, 0% to 50% EtOAc in CH₂Cl₂) togive the impure title material (0.198 g, 66%). The solid was trituratedin hot ethyl acetate to provide the pure title material (0.176 g). LC(Method A): 2.414 min. HRMS(ESI) calcd for C₂₆H₂₁N₄O₃S [M+H]⁺ m/z469.1334, found 469.1379. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 2.57 (s, 3H),3.84 (s, 3 H), 5.39 (s, 2 H), 6.46 (d, J=1.96 Hz, 1 H), 6.74 (broad d, 1H), 6.91 (d, J=9.1 Hz, 1 H), 7.34 (s, 1 H), 7.36 (s, 1 H), 7.39-7.46 (m,3 H), 7.80 (d, J=9.1 Hz, 1 H), 7.90-8.0 (m, 2 H), 8.19 (s, 1 H).

Example 2044-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-(tetrahydro-2H-thiopyran-4-yl)thiazole

A mixture of6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol(Example 203B, 0.340 g, 1.15 mmol) and(2-(tetrahydro-2H-thiopyran-4-yl)thiazol-4-yl)methanol (0.266 g, 1.24mmol) in a 100 mL round-bottomed flask fitted with an addition funnelwas maintained under vacuum for 5 min. The flask was then flushed withnitrogen and charged with dry tetrahydrofuran (30 mL) followed bytributylphosphine (0.74 mL, 3.0 mmol) added in one portion. Theheterogeneous mixture was then treated at 22° C. with a solution of1,1′-(azodicarbonyl)-dipiperidine (0.43 g, 1.70 mmol) in tetrahydrofuran(20 mL) added dropwise over 1 h (with a few short sonication periods).The reaction mixture was homogeneous at the end of the addition and wasstirred for another 2 h. The reaction mixture was then partitionedbetween dichloromethane (250 mL) and saturated sodium bicarbonate. Theorganic phase was washed with brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo to give a glassy residue. The residuewas chromatographed on silica gel (elution 0-30% ethylacetate-dichloromethane) to give 0.420 g (74% yield) of the titlematerial as light yellow solid. LC (Method A): 2.561 min. HRMS(ESI):calcd for C₂₅H₂₅N₄O₃S₂ [M+H]⁺ m/z 493.1368, found 493.1388. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 8.53 (s, 1H), 8.01 (d, J=9.4 Hz, 1H), 7.73 (s, 1H),7.26 (s, 1H), 7.18 (d, J=9.4 Hz, 1H), 6.88 (br d, 1H), 6.63 (d, J=2.0Hz, 1H), 5.28 (s, 2H), 3.83 (s, 3H), 3.10-3.18 (m, 1H), 2.75-2.85 (m,2H), 2.65-2.72 (m, 2H), 2.5 (s, 3H), 2.28-2.43 (m, 2H), 1.70-1.90 (m,2H).

Example 2052-Bromo-4-(((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)thiazole

205A. (2-Bromothiazol-4-yl)methanol

To a solution of methyl 2-bromothiazole-4-carboxylate (1.00 g, 4.50mmol) in ethanol (15 mL) at 0° C. was added NaBH₄ (1.022 g, 27.0 mmol).The cooling bath was removed and the reaction mixture was stirred atambient temperature for 15 min and then at 90° C. for 1.5 h. The cooledreaction mixture was treated with acetic acid (5 mL) and then themixture was evaporated to dryness under reduced pressure. The residueobtained was chromatographed on silica gel (ISCO, elution gradient ofethyl acetate in dichloromethane) to give the title material (0.571 g,65%) as a colorless oil. LC (Method A): 1.101 min. LRMS (APCI): calcdfor C₄H₅BrNOS [M+H]⁺ m/z: 193.93, found 193.90. ¹H NMR (400 MHz, CDCl₃)δ ppm: 7.18 (d, J=0.78 Hz, 1H), 4.76 (d, J=1.00 Hz, 2H), 2.28-2.71 (m,1H).

205B. 2-Bromo-4-(bromomethyl)thiazole

A solution of (2-bromothiazol-4-yl)methanol (0.571 g, 2.94 mmol) indichloromethane (8 mL) was cooled to 0° C. and treated with PBr₃ (0.128mL, 1.359 mmol) dropwise over 2 min. After 5 min, the ice bath wasremoved and the solution was stirred at 22° C. for 4 h. The reactionmixture was then poured into a mixture of ethyl acetate and saturatedaqueous sodium bicarbonate, the organic phase was separated, washed withbrine, dried over anhydrous magnesium sulfate and concentrated in vacuo.The residue obtained was chromatographed on silica gel (ISCO, elutiongradient of dichloromethane in hexanes) to give 0.550 g (72%) of thetitle material as a colorless oil. LC (Method B): 1.813 min. LRMS(APCI): calcd for C₄H₄Br₂NS [M+H]⁺ m/z: 255.84. found: 255.80. ¹H NMR(400 MHz, CDCl₃) δ ppm: 7.27 (s, 1H, underneath CHCl₃), 4.54 (s, 2H).

Example 2052-Bromo-4-(((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)thiazole

A mixture of6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol(Example 203B, 0.208 g, 0.704 mmol) and 2-bromo-4-(bromomethyl)thiazole(0.181 g, 0.704 mmol) in DMF (5 mL) was maintained under vacuum for 5min, then the flask was flushed with nitrogen and powdered anhydrouspotassium carbonate (0.291 g, 2.10 mmol) was added all at once. Theresulting mixture was stirred at room temperature for 1.5 h, then it wasquenched with 1 N hydrochloric acid (1 mL) and finally partitionedbetween dichloromethane and saturated aqueous sodium bicarbonate. Theorganic phase was separated, washed with brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue obtained waschromatographed on silica gel (ISCO, elution gradient of ethyl acetatein dichloromethane) to give 0.220 g (66%) of the title material as asolid. LC (Method A): 2.267 min. HRMS(ESI) calcd. for C₂₀H₁₆BrN₄O₃S[M+H]⁺ m/z: 471.0126; found 471.0121. ¹H NMR (400 MHz, CDCl₃) δ ppm:8.18 (s, 1 H), 7.82 (d, J=9.39 Hz, 1H), 7.31 (s, 1H), 7.34 (s, 1H), 6.93(d, J=9.00 Hz, 1H), 6.74-6.79 (m, 1H), 6.40 (d, J=1.96 Hz, 1H),5.27-5.34 (m, 2H), 3.86 (s, 3H), 2.59 (s, 3H).

Example 2062-Chloro-4-(((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)thiazole

The title compound was prepared using 2-chloro-4-(bromomethyl)thiazole,according to the method described in Example 205 above. LC (Method A):2.314 min. HRMS(ESI) calcd. for C₂₀H₁₆ClN₄O₃S [M+H]⁺ m/z 427.0632; found427.0611. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.19 (s, 1H), 7.82 (d, J=9.39Hz, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 6.94 (d, J=9.39 Hz, 1H), 6.77 (s,1H), 6.40 (s, 1H), 5.27 (s, 2H), 3.86 (s, 3H), 2.59 (s, 3H).

Example 2074-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-(4-methylpiperazin-1-yl)thiazole

In a sealed tube,2-bromo-4-(((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)thiazole(Example 205, 0.025 g, 0.053 mmol) in tetrahydrofuran (2 mL) was treatedwith 1-methylpiperazine (8.85 μl, 0.080 mmol) and the resulting mixturewas heated at 80° C. for 16 h. The cooled reaction mixture was quenchedwith 1 N hydrochloric acid (0.5 mL) and then partitioned betweendichloromethane and saturated aqueous sodium bicarbonate. The organicphase was separated, washed with brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The residue obtained waschromatographed on silica gel (ISCO, elution gradient of ethyl acetatein dichloromethane) and the obtained material was triturated with ethylacetate to give (after filtration and drying in vacuo) 0.016 g (60%) ofthe title compound as a solid. LC (Method A): 1.955 min. HRMS(ESI)calcd. for C₂₅H₂₇N₆O₃S [M+H]⁺ m/z: 491.1865; found 491.1876. ¹H NMR (400MHz, CDCl₃) δ ppm: 8.19 (s, 1H), 7.82 (d, J=9.39 Hz, 1H), 7.34 (s, 1H),6.94 (d, J=9.39 Hz, 1H), 6.75 (s, 1H), 6.63 (s, 1H), 6.44 (s, 1H), 5.13(s, 2H), 3.86 (s, 3H), 3.54 (t, J=1.00 Hz, 4H), 2.59 (s, 3H), 2.54 (t,J=4.89 Hz, 4H), 2.36 (s, 3H).

Example 2084-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-(4-(trifluoromethyl)phenyl)thiazole

208A. Ethyl 2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxylate

A solution of 4-(trifluoromethyl)benzothioamide (3.00 g, 14.62 mmol) inTHF (45 mL) was treated at 22° C. with a solution of ethyl3-bromo-2-oxopropanoate (2.202 mL, 17.54 mmol) in THF (5 mL), addeddropwise over 5 min. The resulting mixture was stirred at roomtemperature for 30 min and then it was heated under reflux for 18 h. Thecooled mixture was diluted with ethyl acetate (200 mL), washed withsaturated sodium bicarbonate and brine, dried over anhydrous magnesiumsulfate and evaporated. The residue was purified on the ISCO using aREDISEP® 80 g column (30 to 100% DCM-hexanes) to give the desiredproduct as a yellow solid (2.52 g, 57%). LCMS (APCI): calcd forC₁₃H₁₁F₃NO₂S [M+H]⁺ m/z 302.05, found 302.0. ¹H NMR (CDCl₃, 400 MHz) δppm: 8.23 (s, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 4.47(q, J=7.2 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H).

208B. (2-(4-(Trifluoromethyl)phenyl)thiazol-4-yl)methanol

A solution of ethyl 2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxylate(2.00 g, 6.64 mmol) in dry diethyl ether (120 mL) was cooled to −78° C.under nitrogen and then treated with solid LiAlH₄ (0.756 g, 19.9 mmol)portion-wise over 5 min. After 3 h at −78° C. the reaction mixture wasquenched by the dropwise addition of ethyl acetate (10 mL) over 5 min.After 10 min, water (1 mL) was added dropwise over 10 min, then a 15%aqueous solution of NaOH (1 mL) and finally more water (2.1 mL) wasadded. The cooling bath was then removed and the heterogeneous mixturewas stirred at room temperature for 30 min to give a white suspension.The suspension was then filtered and the filter-cake washed with ether(200 mL). The combined filtrate was washed with brine, dried overanhydrous magnesium sulfate and evaporated to give the desired productas a white solid (1.46 g, 85%). LCMS (APCI): calcd for C₁₁H₉F₃NOS [M+H]⁺m/z 260.028, found 260.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.07 (d, J=8.2Hz, 2H), 7.71 (d, J=8.2 Hz, 2H), 7.28 (s, 1H), 4.87 (d, J=5.5 Hz, 2H),2.31 (t, J=5.5 Hz, 1H).

208C. 4-(Bromomethyl)-2-(4-(trifluoromethyl)phenyl)thiazole

To a stirred solution of(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methanol (0.500 g, 1.93 mmol)in dry DCM (20 mL) under nitrogen was added phosphorous tribromide (0.37mL, 3.86 mmol) and the reaction mixture was stirred at room temperaturefor 16 h. After completion, the mixture was concentrated and theconcentrate partitioned between saturated aqueous sodium bicarbonate andDCM. The organic phase was separated and the aqueous phase wasback-extracted twice with DCM. The combined organic layers were washedwith brine, dried over MgSO₄ and concentrated. The residue was purifiedon the ISCO using a REDISEP® 40 g column (20 to 100% DCM-hexanes) togive the desired product as a white solid (0.196 g, 32%). LCMS (APCI):calcd for C₁₁H₇BrF₃NS [M+H]⁺ m/z 321.94, found 321.9. ¹H NMR (CDCl₃, 400MHz) δ ppm: 8.05-8.11 (m, 2H), 7.68-7.75 (m, 2H), 7.39 (s, 1H), 4.65 (s,2H).

Example 2084-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-(4-(trifluoromethyl)phenyl)thiazole

A mixture of4-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-6-ol(Example 203B, 0.060 g, 0.20 mmol) and4-(bromomethyl)-2-(4-(trifluoromethyl)phenyl)-thiazole (0.072 g, 0.22mmol) in DMF (8 mL) was treated with K₂CO₃ (0.076 g, 0.55 mmol) and theresulting homogenous mixture was stirred at 23° C. for 1 h to give asuspension. After another 3 h the reaction mixture was diluted withdichloromethane (100 mL), washed with water and brine, dried overanhydrous magnesium sulfate and evaporated. The resulting off-whitepowder was suspended in acetonitrile, sonicated, filtered and dried togive the title compound as an off-white solid (0.090 g, 83%). LC (MethodF): 2.453 min. LCMS (APCI): calcd for C₂₇H₂₀F₃N₄O₃S [M+H]⁺ m/z 537.11,found 537.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.20 (s, 1H), 8.07-8.13 (m,J=8.2 Hz, 2H), 7.83 (d, J=9.4 Hz, 1H), 7.70-7.75 (m, J=8.2 Hz, 2H), 7.48(s, 1H), 7.36 (s, 1H), 6.95 (d, J=9.4 Hz, 1H), 6.78 (dd, J=2.0, 0.8 Hz,1H), 6.49 (d, J=2.0 Hz, 1H), 5.39-5.45 (m, 2H), 3.87 (s, 3H), 2.60 (s,3H).

Example 2092-(4-Chlorophenyl)-4-(((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)thiazole

209A. Ethyl 2-(4-chlorophenyl)thiazole-4-carboxylate

The compound was prepared according to the method described in Example208A. The crude material was purified on the ISCO using a REDISEP® 120 gcolumn (30 to 100% DCM-hexanes) to give the desired product as a yellowsolid (3.18 g, 51%). LCMS (APCI): calcd for C₁₂H₁₁ClNO₂S [M+H]⁺ m/z268.01, found 268.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.17 (s, 1H), 7.96(dd, J=8.8, 4.8 Hz, 2H), 7.44 (dd, J=9.2, 4.8 Hz, 2H), 4.46 (q, J=7.0Hz, 2H), 1.44 (t, J=7.1 Hz, 3H).

209B. (2-(4-Chlorophenyl)thiazol-4-yl)methanol

The compound was prepared according to the method described in Example208B. The desired product was isolated as a yellow solid (2.51 g, 93%).LCMS (APCI): calcd for C₁₀H₉ClNOS [M+H]⁺ m/z 226.00, found 226.0. ¹H NMR(CDCl₃, 400 MHz) δ ppm: 7.87-7.91 (m, 2H), 7.39-7.45 (m, 2H), 7.21 (t,J=1.0 Hz, 1H), 4.84 (d, J=5.7 Hz, 2H), 2.31 (t, J=5.7 Hz, 1H).

209C. 4-(Bromomethyl)-2-(4-chlorophenyl)thiazole

The compound was prepared according to the method described in Example208C. The desired product was isolated as a white solid (0.320 g, 83%).LCMS (APCI): calcd for C₁₀H₈BrClNOS [M+H]⁺ m/z 287.92, found 287.9. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 7.90 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz,2H), 7.32 (s, 1H), 4.63 (s, 2H).

Example 2092-(4-Chlorophenyl)-4-(((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)thiazole

The compound was prepared according to the method described in Example208. The crude material was purified on the ISCO using a REDISEP® 12 gcolumn (20 to 100% EtOAc-DCM) and the obtained yellow powder wassuspended in acetonitrile, sonicated, filtered and dried to give thetitle compound as a pale yellow solid (0.087 g, 85%). LC (Method A):2.569 min. LCMS (APCI): calcd for C₂₆H₂₀ClN₄O₃S [M+H]⁺ m/z 503.09, found503.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.20 (s, 1H), 7.92 (d, J=8.8 Hz,2H), 7.83 (d, J=9.4 Hz, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.40 (s, 1H), 7.36(s, 1H), 6.95 (d, J=9.4 Hz, 1H), 6.78 (dd, J=2.0, 0.8 Hz, 1H), 6.48 (d,J=2.0 Hz, 1H), 5.40 (s, 2H), 3.87 (s, 3H), 2.60 (s, 3H).

Example 2104-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-(4-(trifluoromethoxy)phenyl)thiazole

210A. Ethyl 2-(4-(trifluoromethoxy)phenyl)thiazole-4-carboxylate

The compound was prepared according to the method described in Example208A. The residue was purified on the ISCO using a REDISEP® 80 g column(30 to 100% DCM-hexanes) to give the desired product as a white solid(3.75 g, 87%). LCMS (APCI): calcd for C₁₃H₁₁F₃NO₃S [M+H]⁺ m/z 318.03,found 318.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.18 (s, 1H), 8.06 (d, J=9.0Hz, 2H), 7.31 (d, J=9.0, 2H), 4.46 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz,3H).

210B. (2-(4-(Trifluoromethoxy)phenyl)thiazol-4-yl)methanol

The compound was prepared according to the method described in Example208B. The desired product was isolated as a white solid (2.63 g, 82%).LCMS (APCI): calcd for C₁₁H₉F₃NO₂S [M+H]⁺ m/z 276.02, found 276.0. ¹HNMR (CDCl₃, 400 MHz) δ ppm: (d, J=8.1, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.22(s, 1H), 4.84 (d, J=5.5 Hz, 2H), 2.47 (t, J=5.5 Hz, 1H).

210C. 4-(Bromomethyl)-2-(4-(trifluoromethoxy)phenyl)thiazole

The compound was prepared according to the method described in Example208C. The residue was purified on the ISCO using a REDISEP® 40 g column(50 to 100% DCM-hexanes) to give the title compound as a white solid(0.078 g, 22%). LCMS (APCI): calcd for C₁₁H₈BrF₃NOS [M+H]⁺ m/z 337.94,found 338.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.00 (d, J=9.0, 2H), 7.33(s, 1H), 7.30 (d, J=9.0, 2H), 4.64 (s, 2H).

Example 2104-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-(4-(trifluoromethoxy)phenyl)thiazole

The compound was prepared according to the method described in Example208. The residue was purified on the ISCO using a REDISEP® 12 g column(10 to 80% EtOAc-DCM) and the obtained yellow powder was suspended inacetonitrile, sonicated, filtered to give the title compound as a yellowsolid (0.079 g, 71%). LC (Method A): 2.544 min. LCMS (APCI): calcd forC₂₇H₂₀F₃N₄O₄S [M+H]⁺ m/z 553.11, found 553.1. ¹H NMR (CDCl₃, 400 MHz) δppm: 8.20 (s, 1H), 8.02 (d, J=9.0 Hz, 2H), 7.83 (d, J=9.2 Hz, 1H), 7.42(s, 1H), 7.36 (s, 1H), 7.31 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.2 Hz, 1H),6.78 (s, 1H), 6.49 (d, J=2.0 Hz, 1H), 5.41 (s, 2H), 3.87 (s, 3H), 2.60(s, 3H).

Example 2114-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-(pyridin-4-yl)thiazole

211A. Ethyl 2-(pyridin-4-yl)thiazole-4-carboxylate

The compound was prepared according to the method described in Example208A. The residue was purified on the ISCO using a REDISEP® 120 g column(30 to 80% EtOAc-hexanes) to give the desired product as a dark red oil(2.18 g, 43%). LCMS (APCI): calcd for C₁₁H₁₁N₂O₂S [M+H]⁺ m/z 235.05,found 235.1. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.71-8.78 (m, 2H), 8.28 (d,J=0.8 Hz, 1H), 7.85-7.91 (m, 2H), 4.43-4.51 (m, 2H), 1.41-1.48 (m, 3H).

211B. (2-(Pyridin-4-yl)thiazol-4-yl)methanol

A solution of ethyl 2-(pyridin-4-yl)thiazole-4-carboxylate (2.18 g, 9.31mmol) in EtOH (70 mL) in a 250 mL flask under a nitrogen atmosphere wascooled to 0° C. and treated with NaBH₄ (2.11 g, 55.8 mmol) added insmall portions over 10 min. After 10 min at 0° C., the cooling bath wasremoved and the reaction mixture was stirred at 70° C. for 1 h. Thecooled mixture was then quenched with saturated aqueous NH₄Cl (15 mL)and stirred for another 20 min before being extracted with ethyl acetate(100 mL). The organic phase was washed with brine, dried over MgSO₄ andconcentrated to give a tan solid which was triturated in Et₂O to givethe product as a white powder (1.20 g, 67%). LCMS (APCI): calcd forC₉H₉N₂OS [M+H]⁺ m/z 193.04, found 193.1. ¹H NMR (DMSO-d₆, 400 MHz) δppm: 8.69 (d, J=4.4, 2H), 7.85 (d, J=4.4, 2H), 7.66 (d, J=1.1 Hz, 1H),5.47 (t, J=5.7 Hz, 1H), 4.66 (dd, J=5.7, 1.1 Hz, 2H).

Example 2114-(((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)-2-(pyridin-4-yl)thiazole

The title compound was prepared according to the general methoddescribed in Example 36. The crude product was purified on the ISCOusing a REDISEP® 12 g column (0 to 15% MeOH-DCM) and the obtained yellowpowder was suspended in CH₃CN, sonicated, filtered and dried to give thetitle compound as a pale yellow solid (0.079 g, 71%). LC (Method A):2.392 min. LCMS (APCI): calcd for C₂₅H₂₀N₅O₃S [M+H]⁺ m/z 470.12, found470.2. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.70-8.79 (m, 2H), 8.20 (s, 1H),7.81-7.87 (m, 3H), 7.54 (s, 1H), 7.36 (s, 1H), 6.95 (d, J=9.4 Hz, 1H),6.78 (s, 1H), 6.48 (d, J=1.6 Hz, 1H), 5.43 (s, 2H), 3.87 (s, 3H), 2.60(s, 3H).

Example 2122-(4-Fluorotetrahydro-2H-pyran-4-yl)-4-(((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)thiazole

To a solution of6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol(Example 203B, 0.0285 g, 0.096 mmol) and4-(bromomethyl)-2-(4-fluorotetrahydro-2H-pyran-4-yl)thiazole (Example119C, 0.027 g, 0.096 mmol) in DMF (2 mL) under nitrogen was addedpotassium carbonate (0.0306 g, 0.222 mmol) and the resulting reactionmixture was stirred at room temperature for 2.5 h. The crude reactionmixture was then diluted with dichloromethane, washed with water andbrine, dried over MgSO₄, filtered and concentrated. The crude residueobtained was purified by column chromatography (Isco, 12 g cartridge)eluting with a gradient of ethyl acetate in dichloromethane (from 0 to100%). The product obtained from the column chromatography wastriturated in ethanol and the solid was collected by filtration anddried in vacuo to give the pure title compound (0.034 g, 71%). LC(Method A): 2.306 min. HRMS(ESI): calcd for C₂₅H₂₄FN₄O₄S [M+H]⁺ m/z495.1502, found 495.1797. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 2.03-2.15 (m,2H), 2.18-2.40 (m, 2H), 2.54 (s, 3H), 3.65-3.76 (m, 2H), 3.81-3.89 (m,2H), 3.83 (s, 3H), 5.34 (s, 2H), 6.65 (d, J=2.0 Hz, 1H), 6.89-6.91 (m,1H), 7.19 (d, J=9.4 Hz, 1H), 7.28 (s, 1H), 7.97 (s, 1H), 8.01 (d, J=9.0Hz, 1H), 8.54 (s, 1H).

Examples 213 to 242

The following additional Examples have been prepared, isolated andcharacterized according to the methods disclosed above.

HPLC Retention Ex. Structure Formula Calc. [M + H]⁺ m/z Time(Min)/Method LCMS [M + H]⁺ m/z NMR 213

C₂₅H₂₄N₄O₄S 477.1591 2.179/A 477.1643 ¹H NMR (CDCL₃) δ ppm: 1.86-2.0 (m,2 H), 2.04-2.14 (m, 2 H), 2.60 (s, 3 H), 3.28 (tt, J = 11.7, 3.91 Hz, 1H), 3.57 (tt, J = 11.7, 2.0 Hz, 2 H), 3.87 (s, 3 H), 4.05-4.15 (m, 2 H),5.32 (d, J = 1.17 Hz, 2 H), 6.45 (d, J = 1.96 Hz, 1 H), 6.76 (dd, J =1.96, 0.78 Hz, 1 H), 6.94 (d, J = 9.39 Hz, 1 H), 7.29 (br. s, 1 H), 7.33(d, J = 0.78 Hz, 1 H), 7.82 (d, J = 9.39 Hz, 1 H), 8.19 (s, 1 H). 214

C₂₇H₂₂N₄O₄S 499.1435 2.402/A 499.1487 ¹H NMR (CDCl₃) δ ppm: 2.57 (s, 3H), 3.84 (s, 3 H), 3.85 (s, 3 H), 5.36 (s, 2 H), 6.46 (d, J = 1.92 Hz, 1H), 6.74 (br. d, 1 H), 6.91 (d, J = 9.3 Hz, 1 H), 6.95 (br. d, J = 8.9Hz, 2 H), 7.29 (s, 1 H), 7.33 (s, 1 H), 7.80 (d, J = 9.3 Hz, 1 H), 7.89(br. d, J = 8.9 Hz, 2 H), 8.17 (s, 1 H). 215

C₂₄H₂₃N₅O₄S 478.1544 2.446/A 478.1565 ¹H NMR (400 MHz, CDCl₃) δ ppm:2.57 (s, 3 H), 3.45-3.49 (m, 4 H), 3.80-3.83 (m, 4 H), 3.83 (s, 3 H),5.10 (s, 2 H), 6.42 (d, J = 1.6 Hz, 1 H), 6.63 (s, 1H), 6.72 (br. d, 1H), 6.91 (d, J = 9.46 Hz, 1 H), 7.31 (s, 1 H), 7.80 (d, J = 9.46 Hz, 1H), 8.16 (s, 1 H). 216

C₂₆H₂₇N₅O₄S 506.1857 2.479/A 506.1874 ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s,1H), 7.82 (d, J = 9.4 Hz, 1H), 7.34 (s, 1H), 6.94 (d, J = 9.4 Hz, 1H),6.75 (br. d, 1H), 6.64 (s, 1H), 6.44 (d, J = 2.0 Hz, 1H), 5.13 (s, 2H),3.86 (s, 3H), 3.71-3.83 (m, 4H), 2.76 (dd, J = 12.7, 11.2 Hz, 2H), 2.60(s, 3H), 1.27 (d, J = 6.2 Hz, 6H) 217

C₂₄H₂₃FN₅O₃S₂ 494.1315 2.487/A 494.1451 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.18 (s, 1H), 8.06 (d, J = 9.4 Hz, 1H), 7.56 (s, 1H), 7.09 (d, J = 9.4Hz, 1H), 6.73 (br. d, 1H), 6.66 (s, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.16(s, 2H), 3.89-3.97 (m, 4H), 3.86 (s, 3H), 2.75-2.80 (m, 4H), 2.64 (s,3H). 218

C₂₅H₂₅N₅O₄S 492.17 2.386/A 492.1727 ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.18(s, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.50 (s, 1H), 7.05 (d, J = 9.2 Hz,1H), 6.74 (br. d, 1H), 6.61 (s, 1H), 6.49 (d, J = 1.2 Hz, 1H), 5.23 (s,2H), 3.78-3.96 (m, 8H), 3.86 (s, 3H), 2.63 (s, 3H), 2.10-2.15 (m, 2H).219

C₂₇H₂₀N₄O₅S 513.1227 2.574/A 513.1281 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.54 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.83 (s, 1H), 7.46-7.55 (m, 2H),7.31 (d, J = 0.8 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 8.2 Hz,1H), 6.89 (br. d, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.12 (s, 2H), 5.35 (s,2H), 3.83 (s, 3H), 2.53 (s, 3H). 220

C₂₅H₂₂F₃N₅O₄S 546.1417 2.521/A 546.1435 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.18 (s, 1H), 7.82 (d, J = 9.4 Hz, 1H), 7.30 (s, 1H), 6.93 (d, J = 9.4Hz, 1H), 6.76 (s, 1H), 6.49 (s, 1H), 5.14 (s, 2H), 3.87 (s, 3H), 3.80-3.85 (m, 4H), 3.49-3.56 (m, 4H), 2.59 (s, 3H). 221

C₂₈H₂₂N₄O₅S 527.1384 2.513/A 527.0872 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.20 (s, 1H), 7.83 (d, J = 9.0 Hz, 2H), 7.73-7.77 (m, 1H), 7.47 (br. t,J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 7.15-7.22 (m, 1H), 6.94 (d,J = 9.0 Hz, 1H), 6.77 (br. d, 1H), 6.48 (d, J = 1.6 Hz, 1H), 5.40 (s,2H), 3.87 (s, 3H), 2.60 (s, 3H), 2.35 (s, 3H). 222

C₂₆H₂₀N₄O₄S 485.1278 2.441/A 485.1284 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:9.78 (s, 1H), 8.54 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.89 (s, 1H),7.35-7.41 (m, 2H), 7.26-7.35 (m, 2H), 7.19 (d, J = 9.0 Hz, 1H), 6.84-6.93 (m, 2H), 6.67 (d, J = 2.0 Hz, 1H), 5.38 (s, 2H), 3.84 (s, 3H), 2.53(s, 3H). 223

C₂₉H₂₅N₅O₄S 540.17 2.527/A 540.1686 ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.20(s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 9.4 Hz, 1H), 7.52 (d, J= 8.2 Hz, 2H), 7.43 (s, 1H), 7.36 (s, 1H), 6.94 (d, J = 9.4 Hz, 1H),6.77 (br. d, 1H), 6.49 (d, J = 2.0 Hz, 1H), 5.41 (s, 2H), 3.87 (s, 3H),3.14 (br. s., 3H), 3.02 (br. s., 3H), 2.60 (s, 3H). 224

C₂₇H₁₉N₅O₃S 494.1281 2.556/A 494.1298 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.20 (s, 1H), 8.07-8.13 (m, 2H), 7.83 (d, J = 9.4 Hz, 1H), 7.73-7.79 (m,2H), 7.51 (s, 1H), 7.36 (d, J = 0.8 Hz, 1H), 6.95 (d, J = 9.4 Hz, 1H),6.78 (br. d, 1H), 6.48 (d, J = 2.0 Hz, 1H), 5.42 (s, 2H), 3.87 (s, 3H),2.60 (s, 3H). 225

C₃₀H₂₇N₅O₄S 554.1857 2./A 554.1865 ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.18(s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 9.2 Hz, 1H), 7.50 (d, J= 8.2 Hz, 2H), 7.29 (s, 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.76 (br. s, 1H),6.58 (d, J = 1.6 Hz, 1H), 5.34 (s, 2H), 3.87 (s, 3H), 3.14 (br. s., 3H),3.02 (br. s., 3H), 2.59 (s, 6H). 226

C₂₉H₂₄N₄O₅S 541.154 2.585/A 541.1537 ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.20(s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 9.4 Hz, 1H), 7.45 (d, J= 8.2 Hz, 2H), 7.40 (s, 1H), 7.36 (s, 1H), 6.94 (d, J = 9.4 Hz, 1H),6.77 (br. d, 1H), 6.49 (d, J = 2.0 Hz, 1H), 5.41 (s, 2H), 5.16 (s, 2H),3.87 (s, 3H), 2.60 (s, 3H), 2.15 (s, 3H). 227

C₂₆H₂₀FN₅O₃S 502.1344 2.299/A 502.1344 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.29 (d, J = 5.1 Hz, 1H), 8.18 (s, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.67(d, J = 5.5 Hz, 1H), 7.45 (br. s, 1H), 7.29 (s, 1H), 6.94 (d, J = 9.2Hz, 1H), 6.77 (br. s, 1H), 6.56 (d, J = 2.0 Hz, 1H), 5.36 (s, 2H), 3.87(s, 3H), 2.63 (s, 3H), 2.59 (s, 3H). 228

C₂₅H₁₈FN₅O₃S 488.1187 2.249/A 488.1189 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.81 (d, J = 2.3 Hz, 1H), 8.40 (ddd, J = 8.6, 7.4, 2.3 Hz, 1H), 8.20 (s,1H), 7.83 (d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 7.36 (br. s, 1H), 7.05 (dd,J = 8.6, 3.1 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 6.78 (br.d, 1H), 6.49(d, J = 1.6 Hz, 1H), 5.41 (s, 2H), 3.87 (s, 3H), 2.60 (s, 3H) 229

C₃₀H₂₆N₄O₅S 555.1697 2.573/A 555.1717 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.18 (s, 1H), 7.94 (broad s, 1H), 7.82-7.90 (m, 1H), 7.82 (d, J = 9.4Hz, 1H), 7.38-7.47 (m, 2H), 7.29 (s, 1H), 6.93 (d, J = 9.4 Hz, 1H), 6.76(broad d, 1H), 6.59 (d, J = 2.0 Hz, 1H), 5.34 (s, 2H), 5.17 (s, 2H),3.87 (s, 3H), 2.59 (s, 3H), 2.58 (s, 3H), 2.14 (s, 3H). 230

C₂₈H₂₄N₄O₄S 513.1591 2.472/A 513.1593 ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.55 (s, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.89 (s, 1H), 7.76 (broad d, J =7.4 Hz, 1H), 7.37-7.49 (m, 2H), 7.21 (s, 1H), 7.17 (d, J = 9.2 Hz, 1H),6.89 (broad s, 1H), 6.71 (d, J = 1.6 Hz, 1H), 5.34 (t, J = 5.5 Hz, 1H),5.33 (s, 2H), 4.57 (d, J = 5.5 Hz, 2H), 3.84 (s, 3H), 2.57 (s, 3H), 2.52(s, 3H). 231

C₂₆H₂₁N₅O₃S 484.1438 2.111/A 484.1446 ¹H NMR (400 MHz, CDCl₃) δ ppm:9.07 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 8.16 (dd, J = 8.2, 2.1 Hz, 1H),7.83 (d, J = 9.2 Hz, 1H), 7.43 (br. s, 1H), 7.36 (s, 1H), 7.26 (d, 1H),6.94 (d, J = 9.2 Hz, 1H), 6.77 (d, J = 0.8 Hz, 1H), 6.49 (d, J = 0.8 Hz,1H), 5.41 (s, 2H), 3.87 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H). 232

C₂₅H₁₉N₅O₃S 470.1281 2.127/A 470.1285 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.68-8.80 (m, 2H), 8.20 (s, 1H), 7.82-7.89 (m, 3H), 7.53 (s, 1H), 7.36(s, 1H), 6.95 (d, J = 9.4 Hz, 1H), 6.78 (br.d, 1H), 6.48 (d, J = 2.0 Hz,1H), 5.43 (s, 2H), 3.87 (s, 3H), 2.60 (s, 3H). 233

C₂₅H₁₈ClN₅O₃S 504.0892 2.355/A 504.0892 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.97 (d, J = 2.3 Hz, 1H), 8.25 (dd, J = 8.2, 2.3 Hz, 1H), 8.20 (s, 1H),7.83 (d, J = 9.4 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.35(s, 1H), 6.95 (d, J = 9.4 Hz, 1H), 6.78 (br. d, 1H), 6.48 (d, J = 2.0Hz, 1H), 5.41 (s, 2H), 3.87 (s, 3H), 2.60 (s, 3H). 234

C₂₇H₂₂N₄O₅S₂ 547.1104 2.250/A 547.1126 ¹H NMR (400 MHz, CDCl₃) δ ppm:8.17-8.21 (m, 3H), 8.04 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 9.4 Hz, 1H),7.52 (br. s, 1H), 7.36 (s, 1H), 6.95 (d, J = 9.4 Hz, 1H), 6.78 (br. d,1H), 6.49 (d, J = 1.6 Hz, 1H), 5.43 (s, 2H), 3.88 (s, 3H), 3.11 (s, 3H),2.60 (s, 3H). 235

C₂₅H₂₃F₂N₅O₃S 512.149 2.339/A 512.2 ¹H NMR (CDCl₃, 400 MHz) δ ppm: 8.19(s, 1H), 7.82 (d, J = 9.4 Hz, 1H), 7.34 (s, 1H), 6.94 (d, J = 9.4 Hz,1H), 6.75 (s, 1H), 6.66 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 5.12 (s, 2H),3.86 (s, 3H), 3.65-3.73 (m, 4H), 2.60 (s, 3H), 2.04-2.19 (m, 4H). 236

C₂₅H₂₆N₆O₅S₂ 555.1484 2.205/C 555.1492 ¹H NMR (CDCl₃, 400 MHz) δ ppm:8.54 (s, 1H), 8.01 (d, = 9.2 Hz, 1H), 7.27 (d, J = 0.8 Hz, 1H), 7.19 (d,J = 9.2 Hz, 1H), 7.03 (s, 1H), 6.87 (s, 1H), 6.59 (d, J = 2.0 Hz, 1H),5.09 (s, 2H), 3.82 (s, 3H), 3.51- 3.59 (m, 4H), 3.22-3.29 (m, 4H), 2.92(s, 3H), 2.54 (s, 3H). 237

C₃₁H₂₇N₇O₅S₂ 642.1593 2.344/C 642.1605 ¹H NMR (CDCl₃, 400 MHz) δ ppm:8.17 (s, 1H), 7.85-7.94 (m, 5H), 7.65 (br. s., 1H), 7.18 (d, J = 9.8 Hz,1H), 6.71 (s, 1H), 6.68 (s, 1H), 6.42 (d, J = 1.6 Hz, 1H), 5.07 (s, 2H),3.84-3.88 (m, 3H), 3.64-2.70 (m, 4H), 3.20-3.25 (m, 4H), 2.67 (s, 3H).238

C₂₆H₂₇N₅O₄S 506.1862 2.214/C 506.1864 ¹H NMR (CDCl₃, 400 MHz) δ ppm:8.17 (s, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.28 (s, 1H), 6.93 (d, J = 9.2Hz, 1H), 6.74 (s, 1H), 6.53 (d, J ≦ 2.0 Hz, 1H), 5.06 (s, 2H), 3.87 (s,3H), 3.79-3.85 (m, 4H), 3.42- 3.48 (m, 4H), 2.79 (q, J = 7.4 Hz, 2H),2.59 (s, 3H), 1.23 (t, J = 7.4 Hz, 3H). 239

C₂₆H₂₄F₂N₄O₃S 511.1615 2.509/F 511.1652 ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:8.54 (s, 1H), 8.01 (d, J = 9.4 Hz, 1H), 7.74 (s, 1H), 7.26 (d, J = 0.8Hz, 1H), 7.19 (d, J = 9.4 Hz, 1H), 6.88 (d, J = 0.8 Hz, 1H), 6.63 (d, J= 1.6 Hz, 1H), 5.29 (s, 2H), 3.83 (s, 3H), 3.25 (m, 1H), 2.54 (s, 3H),2.19-1.92 (m, 6H), 1.77 (m, 2H). 240

C₃₁H₂₇ClN₄O₄S 587.1520 2.009/F 587.1564 ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:8.53 (s, 1H), 8.01 (d, J = 9.4 Hz, 1H), 7.80 (s, 1H), 7.43-7.35 (m, 3H),7.30 dt, J = 2.0, 7.0 Hz, 1H), 7.26 (d, J = 0.8 Hz, 1H), 7.19 (d, J =9.4 Hz, 1H), 6.88 (m, 1H), 6.65 (d, J = 2.0 Hz, 1H), 5.32 (s, 2H), 3.82(s, 3H), 3.74 (m, 2H), 3.56 (m, 2H), 2.60 (m, 2H), 2.54 (s, 3H), 2.35(m, 2H). 241

C₃₀H₂₅ClN₄O₄S 573.1363 2.564/F 573.1397 ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:8.54 (s, 1H), 8.01 (d, J = 9.4 Hz, 1H), 7.77 (s, 1H), 7.41 (s, 4H), 7.26(s, 1H), 7.19 (d, J = 9.4 hz, 1H), 6.88 (d, J = 0.8 Hz, 1H), 6.63 (d, J= 2.0 Hz, 1H), 5.28 (s, 2H), 4.59 (d, J = 8.6 Hz, 1H), 4.12 (d, J = 8.6Hz, 1H), 3.97-3.88 (m, 1H), 3.82 (s, 3H), 3.00 (m, 1H), 2.58 (m, 1H),2.54 (s, 3H). 242

C₃₂H₃₀N₄O₄S 567.2066 2.622/F 567.2117 ¹H NMR (DMSO-d₆, 400 MHz) δ ppm:8.54 (s, 1H), 8.01 (d, J = 9.4 Hz, 1H), 7.74 (s, 1H), 7.31 (m, 1H), 7.27(d, J = 9.4 Hz, 2H), 7.19 (d, J = 9.4 Hz, 1H), 7.14 (d, J = 8.2 Hz, 2H),6.88 (d, J = 1.2 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 5.30 (s, 2H), 3.82(s, 3H), 3.74-3.68 (m, 2H), 3.58 (m, 2H), 2.57 (m, 2H), 2.54 (s, 3H),2.33 (m, 2H), 2.25 (s, 3H).

Examples 243 to 286 are prepared according to the following procedure

2-Bromo-4-(((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)oxy)methyl)thiazole(Example 205, 15 mg, 0.031 mmol) in dioxane (0.6 mL) was added into aWheaton tube (16×100 mm) which contains an amine (0.108 mmol) and a stirbar. Then potassium butoxide (8.1 mg, 72 μmol) andpalladium-chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-t-butyl ether adduct (2.1 mg, 2.9 μmol) were added into thesolution. All tubes were capped and heated at 105° C. in a heating blockovernight. All samples were dried by a stream of nitrogen, dissolved inDMF (1.0 mL), filtered with Whatman 0.45 um PVDF filter, and purified bypreparative HPLC.

Examples 287 to 317 are prepared according to the following procedure

HATU (9.71 mg, 26 μmol) and DIPEA (14 μA, 79 μmol) was added to asolution of4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)benzoicacid (Example 39D, 10.5 mg, 20 mmol) in DMF (0.6 mL) in a Wheaton tube(16×100 mm). The mixture was stirred at rt for 5 minutes and then thesolution of the amine (200 μmol) in DMF was added and the tube wascapped and shaken for 2 hours at rt. The crude reaction mixture waspurified by preparative HPLC.

In the structures set forth below for Examples 243 to 317, the “−0”attached to a carbon atom is used to denote an “—OH” group. Similarly,in the structures set forth below for Examples 243 to 317, the “N”attached to a carbon atom is used to denote an “NH” moiety.

HPLC LCMS reten- [M + tion HPLC Formula H]⁺ time Meth- Ex. StructureWeight m/z (min) od 243

520.61  521.23 2.50 G 244

520.61  521.23 4.12 G 245

498.57  499.19 2.64 H 246

523.61  524.24 3.03 G 247

554.63  553.34 4.45 G 248

526.62  527.23 4.60 G 249

465.53  466.18 4.13 G 250

474.54  475.17 4.12 G 251

465.53  466.14 4.12 G 252

518.64  519.26 2.36 H 253

477.54  478.22 4.10 G 254

532.62  533.23 4.11 G 255

449.53  450.19 3.08 G 256

491.57  492.20 4.26 G 257

447.52  448.02 2.96 H 258

493.61  494.21 3.15 H 259

489.60  490.26 4.74 G 260

508.56  509.21 3.14 H 261

522.59  523.20 2.96 H 262

552.66  553.03 3.54 H 263

553.64  554.01 3.27 H 264

512.59  513.26 4.73 G 265

519.53  520.19 3.33 H 266

515.57  516.23 3.36 H 267

497.58  498.22 4.59 G 268

587.10  587.17 3.68 H 269

540.65  541.27 3.22 H 270

567.67  568.26 2.86 H 271

503.63  504.05 3.74 H 272

493.56  494.24 3.11 H 273

560.68  561.02 2.77 H 274

475.57  476.04 3.31 H 275

475.57  476.06 3.31 H 276

504.61  505.24 4.34 G 277

491.57  492.22 4.38 G 278

501.61  502.24 3.52 H 279

435.51  436.21 2.88 H 280

463.56  464.06 3.30 H 281

540.63  541.16 4.37 G 282

516.56  517.18 4.65 G 283

513.58  514.21 3.17 H 284

588.09  587.96 3.62 H 285

567.67  568.24 4.60 G 286

560.68  561.28 2.77 H 287

603.723  604.4 3.38 H 288

586.6521 587.4 3.04 H 289

573.6533 574.4 3.00 H 290

589.6527 590.4 4.06 G 291

623.6611 624.5 4.31 G 292

614.7059 615.5 4.17 G 293

577.6417 578.4 4.05 G 294

603.6796 604.4 4.24 G 295

589.6527 590.5 3.87 G 296

587.6802 588.4 4.36 G 297

603.723  604.5 4.52 G 298

603.6796 604.4 4.13 G 299

601.7071 602.5 4.43 G 300

591.6686 592.5 4.09 G 301

587.6802 588.7 4.42 G 302

615.734  616.4 4.53 G 303

615.734  616.4 4.50 G 304

575.6692 576.4 4.28 G 305

615.6137 616.5 4.35 G 306

561.6423 562.4 4.20 G 307

604.7108 605.5 4.04 G 308

575.6692 576.4 4.27 G 309

603.723  604.5 4.54 G 310

589.6961 590.5 4.37 G 311

714.7029 601.5 4.12 G 312

615.734 616.4 4.53 G 313

643.7877 644.4 4.68 G 314

601.7071 602.3 4.45 G 315

573.6533 574.3 4.26 G 316

613.7181 614.4 4.45 G 317

615.734 616.3 4.50 G

Example 318 Tritium Labeled2-Methoxy-6-(6-methoxy-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A Trisorber flask with stirbar was charged with2-methoxy-6-(6-methoxy-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(Example 3, 0.50 mg, 1.02 μmol) and Crabtree's catalyst(((SP-4)tris(cyclohexyl)phosphane[(1-2-η:5-6-η))-cycloocta-1,5-diene]pyridineiridiumhexafluoridophosphate) (2.3 mg, 2.86 μmol). To this was added CH₂Cl₂(0.50 ml) by syringe. The flask was attached to the Trisorber andsubmitted to freeze, pump and thaw cycles to remove dissolved gases. Tothe reaction mixture was added 1.0 Ci of Tritium gas and the mixture wasstirred at room temperature. After 18 h, the CH₂Cl₂ was removed byrotovap. The crude product was dissolved in ethanol and the labiletritium was exchanged as the ethanol was removed by rotovap. This wasrepeated two additional times. The crude product was dissolved in 5.0 mlof ethanol. An aliquot of the crude mixture (20 μl) was diluted in 5.0ml of ethanol. A 20 μl aliquot of this diluted solution was counted byLiquid Scintillation Counting and showed 207 mCi of tritiated materialto be present. HPLC analysis (AGILENT® 1100 HPLC with a BetaRamradiochemical detector, column=PHENOMENEX® Luna 5 um C18(2), 250×4.6 mmMobile Phase A=100 Water: 1 TFA, Mobile Phase B=1000 Acetonitrile: 1TFA. Gradient=0 min 90% B, 8 min 90% B, 15 min 100% B, flowrate=1.0ml/min) showed the crude product mixture contained 8.5% of the desiredproduct (retention time=6.4 min). The crude product was purified bySemi-preparative HPLC (AGILENT® 1100 HPLC, Column ═PHENOMENEX® Luna, 5um C18(2), 10×250 mm, Mobile phase A=700 CH₃CN:300 Water with 0.1% TFA,Mobile phase B=MeOH, Gradient=0 min 100% A, 25 min 100% A, 30 min 100%B, Flowrate=4.0 ml/min, UV detection at 305 nm. The fractions containingproduct were collected with retention times between 20.2 to 23.5 min.Collected fractions were pooled and the solvent removed by rotovap. Theresulting product was dissolved in 8.5 ml of 90:10 Ethanol:Water toproduce a 1.0 mCi/ml solution, 8.5 mCi total. HPLC/Rad analysis(AGILENT® 1100 HPLC system, column=PHENOMENEX® Luna 5 um C18(2), 4.6×150mm, Mobile phase A=Water 1000:1 TFA, Mobile phase D=Acetonitrile.Gradient=0 min 65% D, 20 min 65% D, 25 min 100% D, 35 min 100% D,flowrate=1.2 ml/min; UV detection at 305 nm, retention time=11.95 min,99.74% radiochemically pure. LC/MS analysis (+ ion) showedm/z=491/492/493/494/495/486/497/498/499. The specific activity wasdetermined by LC/MS by comparison to the LC/MS analysis of unlabeledExample 3 and was 42.5 Ci/mmol. ³H-NMR (320 MHz, DMSO-D₆) δ 8.02 (s, T),7.09 (s, T).

Biology

The term “PAR4 antagonist” denotes an inhibitor of platelet aggregationwhich binds PAR4 and inhibits PAR4 cleavage and/or signaling. Typically,PAR4 activity is reduced in a dose dependent manner by at least 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to suchactivity in a control cell. The control cell is a cell that has not beentreated with the compound. PAR4 activity is determined by any standardmethod in the art, including those described herein (for example calciummobilization in PAR4 expressing cells, platelet aggregation, plateletactivation assays measuring e.g., calcium mobilization, p-selectin orCD40L release, or thrombosis and hemostasis models). The term “PAR4antagonist” also includes a compound that inhibits both PAR1 and PAR4.

It is desirable to find compounds with advantageous and improvedcharacteristics compared with known anti-platelet agents, in one or moreof the following categories that are given as examples, and are notintended to be limiting: (a) pharmacokinetic properties, including oralbioavailability, half life, and clearance; (b) pharmaceuticalproperties; (c) dosage requirements; (d) factors that decrease bloodconcentration peak-to-trough characteristics; (e) factors that increasethe concentration of active drug at the receptor; (f) factors thatdecrease the liability for clinical drug-drug interactions; (g) factorsthat decrease the potential for adverse side-effects, includingselectivity versus other biological targets; (h) improved therapeuticindex with less propensity for bleeding; and (h) factors that improvemanufacturing costs or feasibility.

The term “compound”, as used herein, means a chemical, be itnaturally-occurring or artificially-derived. Compounds may include, forexample, peptides, polypeptides, synthetic organic molecules, naturallyoccurring organic molecules, nucleic acid molecules, peptide nucleicacid molecules, and components and derivatives thereof.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or nonhumanorganism that could potentially benefit from treatment with a PAR4antagonist. Exemplary subjects include human beings of any age with riskfactors for cardiovascular disease, or patients that have alreadyexperienced one episode of cardiovascular disease. Common risk factorsinclude, but are not limited to, age, male sex, hypertension, smoking orsmoking history, elevation of triglycerides, elevation of totalcholesterol or LDL cholesterol.

In some embodiments, the subject is a species having a dual PAR1/PAR4platelet receptor repertoire. As used herein, the term “dual PAR1/PAR4platelet receptor repertoire” means that a subject expresses PAR1 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR1/PAR4 platelet receptor repertoire include human beings, non-humanprimates, and guinea pigs.

In other embodiments, the subject is a species having a dual PAR3/PAR4platelet receptor repertoire. As used herein, the term “dual PAR3/PAR4platelet receptor repertoire” means that a subject expresses PAR3 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR3/PAR4 platelet receptor repertoire include rodents and rabbits.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting its development; and/or(b) relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit and/or antagonize PAR4 and/or toprevent or treat the disorders listed herein. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi) within a blood vessel that may causeischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population. (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl.J. Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA,293(6):715-722 (2005).) Hence, the most common cancers associated withthrombosis in men are prostate, colorectal, brain, and lung cancer, andin women are breast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular weight heparin preparations have been approvedby the FDA for these indications.

The term “pharmaceutical composition”, as used herein, means anycomposition, which contains at least one therapeutically or biologicallyactive agent and is suitable for administration to the patient. Any ofthese formulations can be prepared by well-known and accepted methods ofthe art. See, for example, Gennaro, A. R., ed., Remington: The Scienceand Practice of Pharmacy, 20th Edition, Mack Publishing Co., Easton, Pa.(2000).

The invention includes administering to a subject a pharmaceuticalcomposition that includes a compound that binds to PAR4 and inhibitsPAR4 cleavage and/or signaling (referred to herein as a “PAR4antagonist” or “therapeutic compound”).

The compounds of this disclosure can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The preferred dose of the PAR4 antagonist is a biologically active dose.A biologically active dose is a dose that will inhibit cleavage and/orsignaling of PAR4 and have an anti-thrombotic effect. Desirably, thePAR4 antagonist has the ability to reduce the activity of PAR4 by atleast 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or morethan 100% below untreated control levels. The levels of PAR4 inplatelets is measured by any method known in the art, including, forexample, receptor binding assay, platelet aggregation, plateletactivation assays (e.g., p-selectin expression by FACS), Western blot orELISA analysis using PAR4 cleavage sensitive antibodies. Alternatively,the biological activity of PAR4 is measured by assessing cellularsignaling elicited by PAR4 (e.g., calcium mobilization or other secondmessenger assays).

In some embodiments, a therapeutically effective amount of a PAR4compound is preferably from about less than 100 mg/kg, 50 mg/kg, 10mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In a more preferredembodiment, the therapeutically effective amount of the PAR4 compound isless than 5 mg/kg. In a most preferred embodiment, the therapeuticallyeffective amount of the PAR4 compound is less than 1 mg/kg. Effectivedoses vary, as recognized by those skilled in the art, depending onroute of administration and excipient usage.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration may contain a water soluble saltof the active ingredient, suitable stabilizing agents, and if necessary,buffer substances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Dispersion

A spray dried dispersion can be prepared for oral administration bymethods know to one skilled in the art.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, IA, IB, IC, ID, IE or IF,preferably, a compound selected from one of the examples, generally theamount of each component in a typical daily dosage and typical dosageform may be reduced relative to the usual dosage of the agent whenadministered alone, in view of the additive or synergistic effect of thetherapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the examples and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Additionally, certain compounds disclosed herein may be useful asmetabolites of other compounds. Therefore, in one embodiment, compoundsmay be useful either as a substantially pure compound, which may alsothen be incorporated into a pharmaceutical composition, or may be usefulas metabolite which is generated after administration of the prodrug ofthat compound. In one embodiment, a compound may be useful as ametabolite by being useful for treating disorders as described herein.

The activity of the PAR4 antagonists of the present invention can bemeasured in a variety of in vitro assays. Exemplary assays are shown inthe Examples below.

The FLIPR assay is an exemplary in vitro assay for measuring theactivity of the PAR4 antagonists of the present invention. In thisassay, intracellular calcium mobilization is induced in PAR4 expressingcells by a PAR4 agonist and calcium mobilization is monitored. See,e.g., Example A.

AYPGKF is a known PAR4 agonist. An alternative PAR4 agonist isH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂. As shown in ExampleB below, H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ wasvalidated as a PAR4 agonist in the FLIPR assay. A side-by-sidecomparison of the IC₅₀ values of ˜180 compounds were performed usingAYPGKF versus H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂. Theresults demonstrated a strong correlation between the two assays.Additionally, H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ hasimproved agonist activity as compared to AYPGKF with an EC₅₀ that is 10fold lower than the EC₅₀ for AYPGKF in the FLIPR assay.H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ can be synthesizedusing methods well known to those of skill in the art.

The FLIPR assay can also be used as a counterscreen to test agonistactivity or PAR1 antagonist activity in a cell line that expresses bothPAR1 and PAR4. The PAR1 antagonist activity can be tested by the abilityof the compound to inhibit calcium mobilization induced by the PAR1agonist peptide SFLLRN or other PAR1 agonist peptides.

The compounds of the current invention can be tested in vitro for theirability to inhibit platelet aggregation induced by gamma-thrombin asshown in Example C. Gamma-thrombin, a proteolytic product ofalpha-thrombin which no longer interacts with PAR1, selectively cleavesand activates PAR4 (Soslau, G. et al., “Unique pathway ofthrombin-induced platelet aggregation mediated by glycoprotein Ib”, J.Biol. Chem., 276:21173-21183 (2001)). Platelet aggregation can bemonitored in a 96-well microplate aggregation assay format or usingstandard platelet aggregometer. The aggregation assay can also beemployed to test the selectivity of the compound for inhibiting plateletaggregation induced by PAR4 agonist peptides, PAR1 agonist peptide, ADP,or thromboxane analogue U46619.

Example D is an alpha-thrombin-induced platelet aggregation assay.Alpha-thrombin activates both PAR1 and PAR4. The ability of a selectivePAR4 antagonist of the present invention, namely, the Example 3 compoundto inhibit platelet aggregation was measured using a standard opticalaggregometer. Inhibition of alpha-thrombin induced platelet aggregationby the Example 3 compound is shown in FIGS. 1A and 1B. The data shows,for the first time in the art, that a PAR4 antagonist alone caneffectively inhibit platelet aggregation. The extent of plateletinhibition by the PAR4 antagonist is at least comparable to what hasbeen previously described for PAR1 antagonists.

Example E is a tissue factor-induced platelet aggregation assay. Theconditions in this assay mimic the physiological events during thrombusformation. In this assay, platelet aggregation in human PRP wasinitiated by the addition of tissue factor and CaCl₂. Tissue factor, theinitiator of the extrinsic coagulation cascade, is highly elevated inhuman atherosclerotic plaque. Exposure of blood to tissue factor at theatherosclerotic site triggers a robust generation of thrombin andinduces the formation of obstructive thrombi.

The efficacy of the PAR4 antagonists of the present invention inpreventing thrombosis can also be measured in a variety of in vivoassays. Exemplary mammals that can provide models of thrombosis andhemostasis to test the effectiveness of the PAR4 antagonists of thepresent invention as antithrombotic agents include, but are not limitedto, guinea pigs and primates. Relevant efficacy models include, but arenot limited to, electrolytic injury-induced carotid artery thrombosis,FeCl₃-induced carotid artery thrombosis and arteriovenous-shuntthrombosis. Models of kidney bleeding time, renal bleeding time andother bleeding time measurements can be used to assess the bleeding riskof the antithrombotic agents described in the current invention. ExampleG describes an in vivo model of arterial thrombosis in cynolmolgusmonkeys. Compounds of the present invention can be tested in this modelfor their ability to inhibit thrombus formation induced by electrolyticinjury of the carotid artery. Demonstration of efficacy in this modelsupports the utility of PAR4 antagonists of the present invention fortreatment of thromboembolic diseases.

Assays

Materials

1) PAR1 and PAR4 Agonist Peptides

SFFLRR is a known high affinity PAR1 selective agonist peptide.(Reference: Seiler, S. M., “Thrombin receptor antagonists”, Seminars inThrombosis and Hemostasis, 22(3):223-232 (1996).) The PAR4 agonistpeptides AYPGKF and H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂were synthesized. H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂showed improved PAR4 agonist activity over AYPGKF in the FLIPR assay(EC₅₀ of 8 μM for H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and60 μM for AYPGKF) and in washed platelet aggregation assay (EC₅₀ of 0.9μM for H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 12 μM forAYPGKF).

2) PAR4 Expressing Cells

HEK293 cells stably expressing PAR4 were generated by a standard methodof transfection of human F2R23 cDNA expression vector or by RAGEtechnology from Athersys Inc. (Cleveland, Ohio) and selected based onPAR4 protein expression of mRNA expression. Those cells demonstratedfunctional responses to PAR4 agonist peptide-induced intracellularcalcium elevation using FLIPR (Fluorometric Imaging Plate Reader;Molecular Devices Corp.). These cells express endogenous PAR1 and canelicit calcium signal upon stimulation with PAR1 agonist peptide. Cellswere grown in Dulbecco's Modified Eagle's Medium (DMEM) (Invitrogen,Carlsbad, Calif.), 10% FBS, 1% PSG, 3 μg/ml puromycin and 25 nMMethotrexate) at 37° C. with 5% CO₂.

3) Preparation of Platelet Rich Plasma (PRP)

Human blood was collected in 3.8% sodium citrate at a ratio of 1 ml per9 ml blood. The platelet rich plasma was isolated by centrifugation at170 g for 14 minutes.

4) Preparation of Washed Platelets (WP)

Human blood was collected in ACD (85 mM tri-sodium citrate, 78 mM citricacid, 110 mM D-glucose, pH 4.4) at a ratio of 1.4 ml per 10 ml blood.PRP was isolated by centrifugation at 170 g for 14 minutes and plateletswere further pelleted by centrifugation at 1300 g for 6 minutes.Platelets were washed once with 10 ml ACD containing 1 mg/ml bovineserum albumin. Platelets were resuspended at ˜2.5×10⁸/ml in Tyrode'sBuffer (137 mM NaCl, 2 mM KCl, 1.0 mM MgCl₂, 1 mM CaCl₂, 5 mM glucose,20 mM HEPES pH 7.4).

Example A FLIPR Assay in PAR4-Expressing HEK293 Cells

The activity of the PAR4 antagonists of the present invention weretested in PAR4 expressing cells by monitoringH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂-induced intracellularcalcium mobilization using FDSS6000 (Hamamatsu Photonics, Japan) byfluo-4. Counter screens for agonist activity and PAR1 antagonistactivity were also performed. Briefly, HEK293 EBNA PAR4 clone 20664.1Jcells were plated 24 hrs. prior to experiment in 384 well, Poly-D-Lysinecoated, black, clear bottom plates (Greiner Bio-One, Monroe, N.C.).Cells were plated at 20,000 cells/well in 20 μA growth medium andincubated at 37° C. with 5% CO₂ overnight. At time of assay, media wasreplaced with 40 μl 1× Hank's Buffered Saline Solution (HBSS) (with 10mM HEPES) and 20 μl test compound also diluted in 1×HBSS buffer wasadded at various concentrations and 0.67% DMSO final concentration onthe FDSS for agonist measurement. The cells were then incubated for 30minutes at room temperature followed by addition of 20 μl of agonistpeptide for antagonist measurement on the FDSS. The agonist peptideH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ for PAR4 antagonistscreen or SFFLRR for PAR1 counter screen were routinely tested to ensurea response at EC₅₀ in the assay (˜2.5 μM forH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 600 nM forSFFLRR).

Example B Validation ofH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ as a PAR4 Agonist

To validate H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ as a PAR4agonist in the FLIPR assay, side-by-side comparison of the IC₅₀ valuesof ˜180 compounds were performed using AYPGKF versusH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂. The resultsdemonstrated a strong correlation between the two assays (Spearman'srank correlation coefficient rho=0.7760, p<0.0001). The relevance of theFLIPR assay in the HEK293 cells was confirmed by a direct assayconnectivity to the washed platelet assay. The IC₅₀ values of ˜200compounds from AYPGKF FLIPR assay was strongly correlated to that fromAYPGKF washed platelet aggregation assay (Spearman's rank correlationcoefficient rho=0.836, p<0.001). Similar results were obtained comparingFLIPR and washed platelet data usingH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂.

Example C Gamma Thrombin Induced Platelet Aggregation Assays

The ability of the compounds of the current invention to inhibitplatelet aggregation induced by gamma-thrombin was tested in a 96-wellmicroplate aggregation assay format. Briefly, PRP or washed plateletsuspension (100 μl) was pre-incubated for 5 minutes at room temperaturewith varying concentrations of compounds. Aggregation was initiated by˜10-50 nM gamma thrombin (Haematologic Technologies, Essex Junction,Vt.), which was titrated daily to achieve 80% platelet aggregation.Refludan at 1 U/mL (Berlex, Montville, N.J.) was added to the gammathrombin sample to prevent PAR1 activation induced by residualalpha-thrombin contamination. The plate was then placed into a 37° C.Molecular Devices (Sunnyvale, Calif.) SPECTRAMAX® Plus Plate Reader. Theplate was mixed for 10 seconds before the first read and 50 secondsbetween each read for up to 15 minutes at 405 nM. Data was collectedwith SOFTMAX® 4.71 software. The plate also included an untreatedcontrol sample which served as ODmax, while buffer containing noplatelets was the ODmin. Platelet aggregation was determined bysubtracting the ODmax from the ODmin for the 100% aggregation value. Inexperimental samples, the observed transmission was subtracted from theminimum value and then compared to the 100% aggregation value todetermine the percentage aggregation. IC₅₀ values are determined usingExcel Fit software.

The aggregation assays were also employed to test the selectivity of thecompound against other platelet receptors by using SFFLRR for PAR1,collagen (Chrono-Log, Havertown, Pa.) for collagen receptors, ADP forP2Y1 and P2Y12 and U46619 (Cayman Chemical, Ann Arbor, Mich.) forthromboxane receptors.

Example D Alpha-Thrombin Induced Platelet Aggregation Assays

The ability of PAR4 antagonist to inhibit platelet aggregation inducedby alpha-thrombin was tested using human washed platelets. Example 3 waspre-incubated with washed platelets for 20 min. Aggregation wasinitiated by addition of 1.5 nM alpha-thrombin (HaematologicTechnologies, Essex Junction, Vt.) to 300 μl of washed platelets atstirring speed of 1000 rpm. Platelet aggregation was monitored usingOptical Aggregometer (Chrono-Log, Havertown, Pa.) and the area under thecurve (AUC) at 6 min was measured. IC₅₀ was calculated using vehiclecontrol as 0% inhibition. The IC₅₀ for the inhibition of plateletaggregation by Example 3 was calculated to be 5 nM (n=3) (FIGS. 1A and1B).

Example E Tissue Factor-Induced Platelet Aggregation Assay

The ability of PAR1 or PAR4 antagonists to inhibit platelet aggregationinduced by endogenous thrombin can be tested in a tissue factor drivenaggregation assay. Aggregation is initiated by addition of CaCl₂ andrecombinant human tissue factor, which results in the generation ofthrombin through activation of the coagulation pathway in the plasma.Anticoagulant agents such as corn trypsin inhibitor (HaematologicTechnologies, Essex Junction, Vt.) at 50 μg/ml and PEFABLOC® FG(Centerchem, Norwalk, Conn.) are also added to the sample to preventfibrin clot formation during the time of the study. Platelet aggregationis monitored using standard instrumentation including opticalaggregometer or impedance aggregometer.

Example F

The following tables set out results obtained employing variouscompounds of the invention tested in the FLIPR assay and the plateletaggregation assay (PRP assay). As indicated above, the FLIPR assay, anin vitro assay, measures the PAR4 antagonist activity of compoundstested as described in Example A. The PRP assay, an in vitro assay,measures the PAR4 antagonist assay of the compounds tested in thepresence of plasma proteins and thrombin agonist as described in ExampleC.

TABLE 1 PAR4 FLIPR assay Example (EC₅₀, nM) 1 1.8 2 0.42 3 0.32 4 1.1 50.61 6 0.68 7 1.5 8 3.9 9 5.3 10 3.5 11 1.3 12 1.3 13 2.1 14 1.2 15 0.9816 3.4 17 1.1 18 2.5 19 1.0 20 1.1 21 0.43 22 0.69 23 0.64 24 1.1 250.55 26 1.8 27 1.6 28 0.51 29 1.4 30 0.65 31 0.59 32 1.3 33 1.7 34 1.235 1.3 36 0.45 37 0.45 38 2.5 39 0.46 40 0.26 41 0.90 42 2.5 43 0.34 440.90 45 1.3 46 2.4 47 0.77 48 0.51 49 0.82 50 0.21 51 0.26 52 0.51 530.52 54 0.36 55 0.79 56 0.24 57 0.67 58 0.33 59 0.47 60 0.38 61 0.64 620.48 63 0.63 64 2.3 65 0.81 66 0.75 67 0.34 68 0.49 69 0.23 70 0.89 710.46 72 0.26 73 0.35 74 0.56 75 0.32 76 0.42 77 1.0 78 0.40 79 2.6 800.74 81 0.85 82 0.67 83 1.1 84 0.97 85 1.1 86 0.30 87 24 88 2.9 89 0.6990 0.33 91 0.27 92 0.63 93 0.45 94 0.43 95 0.83 96 0.64 97 0.63 98 0.3799 0.84 100 0.25 101 0.36 102 2.3 103 0.31 104 0.68 105 0.32 106 0.98107 1.3 108 1.2 109 0.69 110 0.78 111 0.86 112 0.37 113 0.43 114 0.49115 0.33 116 0.32 117 0.43 118 0.33 119 0.72 120 0.45 121 0.27 122 0.72123 0.50 124 0.29 126 0.33 127 1.6 128 0.35 129 0.96 130 0.40 131 0.66132 1.9 133 0.37 134 1.2 135 0.79 136 1.2 137 1.2 138 0.82 139 0.41 1400.67 141 0.47 142 0.31 143 0.39 144 0.26 145 0.45 146 0.73 147 0.96 1480.37 149 4.1 150 0.92 151 0.84 152 0.68 153 1.7 154 1.1 155 0.62 1560.52 157 3.6 158 0.95 159 0.41 160 0.50 161 0.69 162 0.67 163 0.82 1641.3 165 1.1 166 0.97 167 0.26 168 0.28 169 1.3 170 1.7 171 0.27 172 0.94173 0.67 174 24 175 1.4 176 1.3 177 0.61 178 0.87 179 1.0 180 0.47 1810.72 182 0.30 183 0.36 184 0.38 185 0.41 186 0.58 187 1.6 188 0.85 1891.3 190 0.47 191 2.6 192 1.9 193 0.91 194 1.6 195 1.3 196 0.46 197 0.34198 0.42 199 1.1 200 0.51 202 43 203 0.76 204 0.72 205 3.5 206 12 2077.7 208 0.82 209 1.2 210 0.86 211 0.72 212 0.29 213 3.6 214 1.2 215 3.3216 0.99 217 0.61 218 0.56 219 1.0 220 0.72 221 1.2 222 0.65 223 0.62224 0.75 225 0.54 226 0.81 227 0.31 228 0.18 229 0.76 230 1.3 231 1.8232 0.99 233 2.8 234 0.66 235 0.44 236 1.9 237 3.5 238 0.73 239 0.58 2406.9 241 1.2 242 0.59 243 32 244 909 245 5.5 246 1.4 247 0.42 248 3.1 24915 250 3.6 251 11 252 871 253 9.7 254 19 255 1.7 256 7.8 257 7.5 2580.81 259 0.58 260 7.0 261 39 262 0.75 263 1.2 264 207 265 48 266 16 2674.2 268 1.7 269 2.5 270 5.8 271 1.3 272 2.0 273 53 274 3.4 275 4.2 27624 277 1.1 278 1.4 279 7.3 280 6.2 281 0.60 282 3475 283 2.9 284 1.1 2852.9 286 110 287 0.48 288 0.36 289 1.2 290 0.60 291 0.65 292 0.27 2930.72 294 0.40 295 92 296 2.2 297 0.52 298 0.99 299 0.55 300 0.42 3010.63 302 0.44 303 0.85 304 0.88 305 1.0 306 1.2 307 24 308 0.64 309 0.54310 0.53 311 0.65 312 0.77 313 0.43 314 0.37 315 1.3 316 0.95 317 1.6

TABLE 2 PRP assay Example (Gamma Thrombin, IC₅₀, nM) 2 49 3 4.7 6 20348 >3000 9 >3000 10 2700 18 3.6 28 2.9 33 38 34 2324 36 2.1 39 2.1 44 2.048 1.2 56 23 67 2.2 73 1.9 74 0.96 75 1.6 77 1.9 80 0.94 81 1.6 87 >300093 27 94 7.6 103 24 115 28 118 25 121 27 125 5.7 126 1.9 131 >3000 13723 139 26 141 24 145 29 151 26 152 28 161 27 192 28 201 156 202 >3000205 2382 209 23 219 25 243 >3000 244 >3000 245 3132 249 >3000 254 >3000256 >3000 257 >3000 261 >3000 264 >3000 265 >3000 266 >3000 268 2359273 >3000 274 >3000 275 2632 276 >3000 279 >3000 281 >3000 282 >3000 2852338 288 1.0 301 1.9 305 2.0 311 2.0

Example G Cynomolgus Monkey Electrolytic Injury-induced Carotid ArteryThrombosis Model

Healthy cynomolgus monkeys were used in the study. These monkeys wereretired from other pharmacokinetic and pharmacodynamic studies and hadat least a 4-week washout period.

On the day of the study, compounds or vehicles were administered orallyat 1 to 2 hours before the experiment. Monkeys were then sedated byintramuscular administration of 0.2 mg/kg atropine, 5 mg/kg TELAZOL®(tiletamine/zolazepam) and 0.1 mg/kg hydromorphone to facilitateplacement of an endotracheal tube. An intravenous catheter was placed inthe left cephalic vein for fluid administration to prevent dehydration.Animals were then administered with an inhalant anesthetic, isoflurane(1-5% to effect) and oxygen, ventilated, and placed on athermostatically controlled heating pad to maintain the body temperatureat 37° C. General anesthesia was maintained at a surgical plane usinginhaled isoflurane and oxygen. The left brachial artery was cannulatedto record blood pressure and heart rate. Blood pressure and heart ratewere monitored to maintain normal vital signs.

The carotid arterial thrombosis model in monkeys was based on a rabbitarterial thrombosis model, as described by Wong et al. (Wong, P. C. etal., “Nonpeptide factor Xa inhibitors: II. Antithrombotic evaluation ina rabbit model of electrically induced carotid artery thrombosis”, J.Pharmacol. Exp. Ther., 295:212-218 (2002).) Thrombosis was induced byelectrical stimulation of the carotid artery for 5 min at 10 mA using anexternal stainless-steel bipolar electrode. Carotid blood flow wasmeasured with an appropriately sized TRANSONIC® flow probe and aTRANSONIC® perivascular flowmeter (TS420 Model, Transonic Systems Inc.,Ithaca, N.Y.). It was continuously recorded over a 90-min period tomonitor thrombosis-induced occlusion. Integrated carotid blood flow wasmeasured by the area under the flow-time curve. It was expressed aspercent of total control carotid blood flow, which would result ifcontrol blood flow had been maintained continuously for 90 min. Inaddition, thrombus from the injured artery was removed, blotted twice ona weighing paper to remove residual fluid, and weighed. FIG. 1C showsthe results of a dose response experiment with Example 3 in thecynomolgus monkey electrically-induced arterial thrombus model,demonstrating the in vivo antithrombotic efficacy of a PAR4 antagonist.

While it is apparent that the embodiments of the application hereindisclosed are well suited to fulfill the objectives stated above, itwill be appreciated that numerous modifications and other embodimentsmay be implemented by those skilled in the art, and it is intended thatthe appended claims cover all such modifications and embodiments thatfall within the true spirit and scope of the present application.

What we claim is:
 1. A compound, wherein the compound is selected from

or pharmaceutically acceptable salt thereof.
 2. A compound of Formula

or pharmaceutically acceptable salt thereof.
 3. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 2, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.4. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 2. 5. A compound of Formula

or pharmaceutically acceptable salt thereof.
 6. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 5, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.7. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 5. 8. A compound of Formula

or pharmaceutically acceptable salt thereof.
 9. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 8, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.10. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 8. 11. A compound of Formula

or pharmaceutically acceptable salt thereof.
 12. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 11, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.13. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 11. 14. A compound of Formula

or pharmaceutically acceptable salt thereof.
 15. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 14, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.16. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 14. 17. A compound of Formula

or pharmaceutically acceptable salt thereof.
 18. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 17, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.19. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 17. 20. A compound having the formula

or pharmaceutically acceptable salt thereof.
 21. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 20, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.22. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 20. 23. A compound of Formula

or pharmaceutically acceptable salt thereof.
 24. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 23, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.25. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 23. 26. A compound of Formula

stereoisomers or pharmaceutically acceptable salt thereof.
 27. A methodfor the treatment of a thromboembolic disorder or the primary orsecondary prophylaxis of a thromboembolic disorder, which comprises thesteps of administering to a patient in need thereof a therapeuticallyeffective amount of a compound as defined in claim 26, orpharmaceutically acceptable salts thereof, wherein the thromboembolicdisorder is selected from the group consisting of arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, cerebrovascular thromboembolic disorders, andthromboembolic disorders in the chambers of the heart or in theperipheral circulation.
 28. A method of inhibiting or preventingplatelet aggregation, which comprises the step of administering to asubject in need thereof a therapeutically effective amount of a PAR4antagonist, as defined in claim
 26. 29. A compound of Formula

or pharmaceutically acceptable salt thereof.
 30. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 29, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.31. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 29. 32. A compound of Formula

or pharmaceutically acceptable salt thereof.
 33. A method for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which comprises the steps ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 32, or pharmaceuticallyacceptable salts thereof, wherein the thromboembolic disorder isselected from the group consisting of arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, cerebrovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart or in the peripheral circulation.34. A method of inhibiting or preventing platelet aggregation, whichcomprises the step of administering to a subject in need thereof atherapeutically effective amount of a PAR4 antagonist, as defined inclaim
 32. 35. A method for the treatment of a thromboembolic disorder orthe primary or secondary prophylaxis of a thromboembolic disorder, whichcomprises the steps of administering to a patient in need thereof atherapeutically effective amount of a compound as defined in claim 1, orpharmaceutically acceptable salts thereof, wherein the thromboembolicdisorder is selected from the group consisting of arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, cerebrovascular thromboembolic disorders, andthromboembolic disorders in the chambers of the heart or in theperipheral circulation.
 36. A method of inhibiting or preventingplatelet aggregation, which comprises the step of administering to asubject in need thereof a therapeutically effective amount of a PAR4antagonist, as defined in claim
 1. 37. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

where R¹ is OCH₃, —CHFCH₃, or —CF₂CH₃; R² is H; X¹ is CH; X² and X⁴ areboth CH; X³ is CR³; R³ is OCH₃ or fluoro; W is O; R⁴ and R⁵ areindependently selected from H and CH₃;

R⁶ is selected from the group consisting of: a) phenyl substituted by 0to 3 groups independently selected from the group consisting of fluoro,chloro, —CH₃, —CF₃, OH, cyano, —CH₂CN, —OCH₃, —OCF₃, —CH₂OH, —C(CH3)₂OH,—SO₂CH₃ and (C═O)NR¹¹R¹², wherein NR¹¹R¹² is selected from:

b) pyridinyl or pyrimidinyl substituted by 0 to 3 groups independentlyselected from the group consisting of fluoro, chloro, —CH₃ and —OCH₃; c)tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazine substituted by 0 to 3 groups independentlyselected from the group consisting of fluoro, OH, —CH₃ and —NH₂; and d)cyclohexyl substituted by 0 to 3 groups independently selected from thegroup consisting of fluoro, OH and NH₂; and R⁷ is selected from thegroup consisting of H and —CH₃.
 38. A pharmaceutical composition, whichcomprises a pharmaceutically acceptable carrier and a compound asdefined in claim 37, or stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof, alone or in combination withanother therapeutic agent.
 39. A method for the treatment of athromboembolic disorder or the primary or secondary prophylaxis of athromboembolic disorder, which comprises the steps of administering to apatient in need thereof a therapeutically effective amount of a compoundas defined in claim 37, or pharmaceutically acceptable salts thereof,wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, cerebrovascular thromboembolicdisorders, and thromboembolic disorders in the chambers of the heart orin the peripheral circulation.
 40. A method of inhibiting or preventingplatelet aggregation, which comprises the step of administering to asubject in need thereof a therapeutically effective amount of a PAR4antagonist, as defined in claim
 37. 41. A pharmaceutical composition,which comprises a pharmaceutically acceptable carrier and a compound asdefined in claim 2, tautomers, pharmaceutically acceptable salts, orsolvates thereof, alone or in combination with another therapeuticagent.
 42. A pharmaceutical composition, which comprises apharmaceutically acceptable carrier and a compound as defined in claim5, tautomers, pharmaceutically acceptable salts, or solvates thereof,alone or in combination with another therapeutic agent.
 43. Apharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a compound as defined in claim 8, orstereoisomers, tautomers, pharmaceutically acceptable salts, or solvatesthereof, alone or in combination with another therapeutic agent.
 44. Apharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a compound as defined in claim 11, tautomers,pharmaceutically acceptable salts, or solvates thereof, alone or incombination with another therapeutic agent.
 45. A pharmaceuticalcomposition, which comprises a pharmaceutically acceptable carrier and acompound as defined in claim 14, tautomers, pharmaceutically acceptablesalts, or solvates thereof, alone or in combination with anothertherapeutic agent.
 46. A pharmaceutical composition, which comprises apharmaceutically acceptable carrier and a compound as defined in claim17, tautomers, pharmaceutically acceptable salts, or solvates thereof,alone or in combination with another therapeutic agent.
 47. Apharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a compound as defined in claim 20, tautomers,pharmaceutically acceptable salts, or solvates thereof, alone or incombination with another therapeutic agent.
 48. A pharmaceuticalcomposition, which comprises a pharmaceutically acceptable carrier and acompound as defined in claim 23, tautomers, pharmaceutically acceptablesalts, or solvates thereof, alone or in combination with anothertherapeutic agent.
 49. A pharmaceutical composition, which comprises apharmaceutically acceptable carrier and a compound as defined in claim26, or stereoisomers, tautomers, pharmaceutically acceptable salts, orsolvates thereof, alone or in combination with another therapeuticagent.
 50. A pharmaceutical composition, which comprises apharmaceutically acceptable carrier and a compound as defined in claim29, tautomers, pharmaceutically acceptable salts, or solvates thereof,alone or in combination with another therapeutic agent.
 51. Apharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a compound as defined in claim 32, tautomers,pharmaceutically acceptable salts, or solvates thereof, alone or incombination with another therapeutic agent.